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CBD Oil for Diabetes

Can CBD help with diabetes, and, if so, how?  

Diabetes is a group of metabolic diseases known to cause hyperglycemia (high blood sugar levels).

The two primary types of diabetes, type 1 and type 2, are chronic diseases that impact how the body controls blood sugar or glucose. 

Glucose is the fuel that feeds the body's cells, and it needs insulin to enter the cells. 

People with type 1 diabetes cannot produce insulin. Meanwhile, people with type 2 diabetes do not respond to insulin as well as they should, and then, later in the disease, they often do not produce enough insulin. 

The two types of diabetes can lead to chronically high blood sugar levels, which increases the risk of diabetes complications (1). 

Over time, high blood sugar levels result in damage, dysfunction, and even failure of various organs, including the eyes, kidneys, nerves, heart, and brain. 

Having diabetes raises one's risk of heart disease, stroke, kidney disease, and other health problems. 

Having high blood pressure also increases this risk. If one has both diabetes and high blood pressure, these health conditions raise the risk of issues even more.

Can CBD Help with Diabetes? What the Research Says

The initial studies on CBD for diabetes have been promising that, in 2006, Dr Joseph Alpert of the American Journal of Medicine called on the National Institute of Health (NIH) and the Drug Enforcement Administration (DEA) for more funding and collaboration on further research (2).

Insulin resistance is linked with chronic inflammation, as the study published in the Journal of Clinical Investigation indicated (3).

One risk factor for diabetes is obesity, and research published in the American Journal of Medicine in 2013 has shown that CBD has been associated with low levels of fasting insulin and reduced waist circumference (4).

Results of a study in Diabetes, Obesity and Metabolism suggested that the stimulus of cannabinoid receptors CB-1 in the islet (cluster) cells might be linked to insulin production (5).

Meanwhile, in another study published in Clinical Hemorheology and Microcirculation in 2016, CBD was shown to reduce the incidence of diabetes in non-obese diabetic animal models (6). 

In another 2016 study, researchers from the University of Nottingham found that when CBD was used in conjunction with cannabis compound THCV, it helped increase insulin production and lower blood sugar in those with type 2 diabetes (7).

THCV (tetrahydrocannabivarin), as the name suggests, is a cannabinoid similar to THC in molecular structure. Both of these cannabinoids possess psychoactive properties.

The subjects in the said clinical study were required to either not receive any oral hypoglycemic medications or take stable doses of noninsulin glucose-lowering drugs, such as metformin and sulfonylurea, for three months prior to screening.

Results from the study also showed that CBD, when used alone, did not show any detectable metabolic effects.

Why People Are Turning to CBD for Diabetes

With several studies that demonstrate CBD’s therapeutic benefits, its potential to help treat diabetes symptoms cannot be easily overlooked. 


A growing interest in some people is making them look into this natural, non-psychoactive phytocannabinoid as a potential remedy for symptoms or conditions linked to diabetes.


Diabetic complications linked to the endocannabinoid system (ECS) include blindness, atherosclerosis, kidney failure, heart disease, and neuropathic pain (8). 

Meanwhile, CBD’s anti-inflammatory properties might help in managing a diabetes patient’s condition by reducing inflammation.

In a study published in the American Journal of Physiology-Heart and Circulatory Physiology, CBD showed the potential to help reduce the arterial inflammation common in diabetes (9). 

CBD might also reverse the harmful effects of high glucose levels, as a study published in Future Medicinal Chemistry demonstrated (10).

In his work with animal subjects, Dr Raphael Mechoulam and his colleagues noted that CBD not only blocked the onset of diabetes but the development of it as well (11). 

A study demonstrated that CBD helped protect the retinas of diabetic animal subjects (12). 

Diabetes can damage the nerves, resulting in pain from performing normal activities. Thus, people with diabetes often suffer from complications, such as chronic pain in the nerves, which can even be fatal.

However, one study in 2014 showed that CBD and tetrahydrocannabinol might help people suffering from this type of nerve pain (13). 

Participants in the study applied a spray containing both cannabinoids to the areas of their bodies that had diabetic neuropathy. These areas are usually the hands or feet. 

Study participants who had used the CBD and THC spray reported fewer symptoms before the spray. 

More importantly, CBD can help with blood pressure, which increases the risk of having diabetes. 

In a 2017 study published in the journal JCI Insight, results showed that a single dose of CBD reduced resting blood pressure and the blood pressure response to stress (14). 


Previous studies looking at CBD as a means to alleviate diabetes symptoms have shown promising results. However, much of the research was conducted on animals or healthy human volunteers.


A better understanding of how CBD may be used to treat, manage, or prevent diabetes is needed. More extensive and more longitudinal studies, especially on humans with diabetes, or who are at risk of diabetes, are necessary.


Before using CBD as an adjunct diabetes therapy or using CBD alone as a remedy for any existing condition, consult with a doctor experienced in cannabis use. 



  1. Eileen Konieczny and Lauren Wilson. Healing with CBD: How Cannabidiol Can Transform Your Health without the High (California: Ulysses Press, 2018). p60.
  2. Weiss L, Zeira M, Reich S, et al. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity. 2006;39(2):143–151. DOI:10.1080/08916930500356674.
  3. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance [published correction appears in J Clin Invest. 2006 Aug;116(8):2308]. J Clin Invest. 2006;116(7):1793–1801. DOI:10.1172/JCI29069.
  4. Penner EA, Buettner H, Mittleman MA. The impact of marijuana use on glucose, insulin, and insulin resistance among US adults. Am J Med. 2013;126(7):583–589. DOI:10.1016/j.amjmed.2013.03.002.
  5. Jourdan T, Godlewski G, Kunos G. Endocannabinoid regulation of β-cell functions: implications for glycaemic control and diabetes. Diabetes Obes Metab. 2016;18(6):549–557. DOI:10.1111/dom.12646.
  6. Lehmann C, Fisher NB, Tugwell B, Szczesniak A, Kelly M, Zhou J. Experimental cannabidiol treatment reduces early pancreatic inflammation in type 1 diabetes. Clin Hemorheol Microcirc. 2016;64(4):655–662. DOI:10.3233/CH-168021.
  7. Jadoon K et al. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care Oct 2016, 39 (10) 1777-1786; DOI: 10.2337/dc16-0650.
  8. Béla Horváth et al., “The Endocannabinoid System and Plant-Derived Cannabinoids in Diabetes and Diabetic Complications,” The American Journal of Pathology 180, no. 2 (2012): 432–42, DOI:10.1016/j.ajpath.2011.11.003.
  9. Mohanraj Rajesh et al., “Cannabidiol Attenuates High Glucose-Induced Endothelial Cell Inflammatory Response and Barrier Disruption,” American Journal of Physiology-Heart and Circulatory Physiology 293, no. 1 (2007): H610-H619, DOI:10.1152/ajpheart.00236.2007.
  10. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333–1349. DOI:10.4155/fmc.09.93.
  11. Weiss L et al., “Cannabidiol Arrests Onset of Autoimmune Diabetes in NOD Mice,” Neuropharmacology 54, no.1 (2009): 244–49, DOI:10.1016/j.neuropharm.2007.06.029; L. Weiss et al., “Cannabidiol Arrests,” 2006.
  12. Azza B. El-Remessy et al., “Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes,” The American Journal of Pathology 168, no. 1 (2006): 235–44, DOI:10.2353/ajpath. 2006.050500.
  13. Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain. 2014;18(7):999–1012. DOI:10.1002/j.1532-2149.2013.00445.x.
  14. Jadoon KA, Tan GD, O'Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017;2(12):e93760. Published 2017 Jun 15. DOI:10.1172/jci.insight.93760.


   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data Adults Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s) Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis Blood, plasma or serum Urine Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological CNS Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic Acid-base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other

    1. NAME
     1.1 Substance
     1.2 Group
       Antidiabetic agent
     1.3 Synonyms
       Amorph IZS
       Amorphous IZS
       Biphasic Insulin
       Cryst IZS
       Crystalline IZS
       Extended Insulin Zinc Suspension
       Globin Insulin
       Globin Insulin with zinc
       Globin Zinc Injection Insulin
       Globin Zinc Insulin
       Injectio Insulini Protaminati cum zinco
       Insulin cum zinco (crystallisati) suspension
       Insulin Hydrochloride
       Insulin Injection
       Insulin lente
       Insulin semilente
       Insulin Ultralente
       Insulin zinc suspension (mixed)
       Insulin zinci crystallisati suspension injectabilis
       Insulini cum zinco (Amorphi) suspension injectabilis
       Insulini cum zinco suspensio composita
       Insulini Isophani Protaminati Suspension injectabilis
       Insulini Solution Injectabilis
       Insulini Zinci Injectabilis Mixta
       Insulini zinci protaminati injectio
       Insulini zinci protaminati suspension injectabilis PZI
       Isophane Insulin
       Isophane Insulin (NPH)
       Isophane Insulin Suspension
       Isophane Protamine Insulin Injection
       Neutral Insulin
       NPH Insulin
       Ordinary Insulin
       Prompt Insulin Zinc Suspension
       Protamine zinc injection
       Regular Insulin
       Soluble Insulin
       Unmodified Insulin
     1.4 Identification numbers
       1.4.1 CAS number
       1.4.2 Other numbers

     1.5 Brand names, Trade names
       Acid Insulin Injection
            Hypurin Soluble (CP)
            Regular Iletin (Lily USA)
       Highly purified Animal Insulins
            Actrapid MC (Novo UK, Favillon UK)
            Hypurin Neutral (Weddel UK)
            Neusulin (Wellcome UK)
            Nuso Neutral Insulin (Boots UK, Evans Medical UK, 
       Wellcome UK)
            Velosulin (Nordisk UK, Leo UK)
            Velosulin Cartridge (Nordisk, Wellcome)
            Quicksol Boots
            Human Sequence Insulins
            Human Actrapid (Novo)
            Human Actrapid Purified (Novo)
            Human Velosulin (Nordisk, Wellcome)
            Humaline (Lily)
       Highly Purified Animal Insulins
            Insulin zinc suspension Lente (Evans)
            Hypurin Lente (CP)
            Lentard MC (Novo)
            Tempulin (Boots)
            Human sequence insulins
            Human monotard (Novo)
            Humulin Lente (Lily)
            Semitard MC (Novo)
       Human Sequence Insulins
            Human ultratard (Novo)
            Humulin zinc (Lily)
            Rapitard MC (Noro)
            Manufacturers - Boots, Evans Medical UK, Wellcome UK.
       Highly Purified Animal Insulins
            Isophane Insulin Injection (Evans)
            Hypurin Isophane (CP)
            Insulatard (Nordisk, Wellcome)
            Monophane (Boots)
       Mixed Highly Purified Animal Insulins
            Initard 50/50 (Nordisk, Wellcome)
            Mixtard 30/70 (Nordisk, Wellcome)
       Human Sequence Insulins
            Human Insulatard (Nordisk, Wellcome)
            Human Protaphane (Novo)

            Humulin (Lily)
       Mixed Human Sequence Insulins
            Human Actraphane (Noro)
            Human Initard 50/50 (Nordisk, Wellcome)
            Human Mixtard 30/70 (Nordisk, Wellcome)
            Humulin M1 (Lily)
            Humulin M2 (Lily)
            Humulin M3 (Lily)
            Humulin M4 (Lily)
       Hypurin Protamine Zinc (Weddel UK)
            Also Marketed in Great Britain by Boots, Wellcome, Evans 
       Medical and Weddel
       Other Proprietary Names
            Protamine Zinc and Iletin
     1.6 Manufacturers, Importers
       Local agents
       Insulin   Hayleys (Boots)
                 Morrison Son & Jones (Novo)
                 Robert Hall & Co. (Nordisk)
    2. SUMMARY
     2.1 Main risks and target organs
       Hypoglycaemia is the main risk of insulin overdose.  The brain 
       relies on glucose as its source of energy and hypoglycaemia 
       may lead to coma, convulsions and even death.
     2.2 Summary of clinical effects
       The early symptoms of hypoglycaemia are weakness, hunger, 
       giddiness, pallor, sweating, sinking feeling in the stomach, 
       palpitations, irritability, nervousness, headache and tremor.  
       Symptoms resemble those of sympathetic stimulation.
       Later, symptoms such as depression or euphoria, inability to 
       concentrate, blurring of vision, drowsiness, lack of judgement 
       and self control and amnesia may be present due to 
       neuroglycopenia.  Other features are hemiplegia, ataxia, 
       tachycardia, diplopia and paraesthesia.
       If untreated the condition progresses to convulsions, coma and 
       In the precoma stage, Babinski reflex is often present.  
       Pupils are often dilated but react to light.  Later pupils are 
       constricted and no longer react to light.  Hypokalaemia may be 
       Speed of onset of hypoglycaemia varies with the preparation of 
       insulin used.  Symptoms do not usually appear unless the blood 
       glucose concentration falls below 3.5 mmol/l.  Convulsions can 

       occur if the blood glucose concentration falls below 2 mmol/l. 
        In diabetic patients with chronic hyperglycaemia, symptoms of 
       hypoglycaemia may occur at higher blood glucose 
       concentrations.  A few patients may develop hypoglycaemic coma 
       without prior warning symptoms.
       Other effects:
       Non-specific local reactions such as allergic reactions, 
       atrophy of fat or induration and hypertrophy sometimes occur 
       at the site of injection (usually not a problem with highly 
       purified insulins).
     2.3 Diagnosis
       Early symptoms include weakness, hunger, giddiness, pallor, 
       sweating, sinking feeling in the stomach, palpitations, 
       irritability, nervousness, headache and tremor.
       Later, depression or euphoria, inability to concentrate, 
       blurring of vision, drowsiness, lack of judgement and self 
       control and amnesia occur.  Other features are hemiplegia, 
       ataxia, tachycardia, diplopia and paraesthesia.
       If untreated the condition progresses to convulsions, coma and 
       In the precoma stage, Babinski reflex is often present.  
       Pupils are often dilated but react to light.  Later pupils are 
       constricted and no longer react to light.  Hypokalaemia may be 
       Estimation of blood glucose level: (see 2.3.1)
       Estimation of plasma insulin is usually not relevant.  The 
       serum potassium concentration should be measured explicitly. 
       Determination of urinary glucose and ketones for diabetic 
       Serum creatinine, blood urea and serum electrolytes to asses 
       renal function.
     2.4 First aid measures and management principles
       If patient is conscious and cooperative - Oral glucose or 3-4 
       lumps of sugar should be given with water.  This could be 
       repeated in 15 minutes or earlier if symptoms recur.  This 
       should be supplemented by one or more carbohydrate meals until 
       the patient improves.
       If unconscious or uncooperative -  Intravenous glucose or 
       intramuscular glucagon should be given at once.  Hospital 
       admission comes later.  50ml of 50% dextrose should be given 
       NB - It is very important to advise patients and relatives 
       regarding the prevention of hypoglycaemia.  They should know 
       the warning symptoms of hypoglycaemia.

       Correction of hypoglycaemia is the most important aspect of 
       management.  If consciousness is impaired even after 
       correction of hypoglycaemia, cerebral oedema should be 
       suspected.  Cerebral oedema should be treated with mannitol 
       and corticosteroids.
     3.1 Origin of the substance
       Extracted from beta cells of the islets of Langerhans of pork 
       or beef pancreas and purified by crystallisation.
       It is also made biosynthetically by recombinant DNA technology 
       using Escherichia coli or semisynthetically by enzymatic 
       modification of porcine material.
     3.2 Chemical structure
       Molecular weight: 6000
       Consists of two chains, A and B, of amino acids, joined 
       together by two disulphide bonds.  Insulin is synthesised from 
       a single chain precursor named proinsulin.  On conversion of 
       human proinsulin to insulin, 4 basic amino acids and the 
       remaining connector or C peptide is removed by proteolysis.  
       The resultant insulin molecule has 2 chains.  The acidic or A 
       chain with glycine at the amino terminal residue and the basic 
       or B chain consisting of 30 amino acids with phenylalanine at 
       the amino terminus.  An even larger molecule prepoinsulin has 
       been identified as a precursor of proinsulin.
       Insulin can exist as a dimer, monomer or hexamer.  Two 
       molecules of Zn2+ are coordinated in the hexamer which is 
       stored as granules in the beta cell.
       The biologically active form of the hormone is the monomer.
       The porcine hormone is most similar to man and differs only by 
       the substitution of an alanine residue for threonine at the 
       carboxy terminus of the B chain.  Bovine insulin differs by 
       three amino acids and therefore is more antigenic than porcine 
     3.3 Physical properties
       3.3.1 Properties of the substance
             White or almost white crystalline powder.  
             Slightly soluble in water.  Practically 
             insoluble in alcohol, chloroform and ether.  
             Soluble in dilute solution of mineral acids and 
             with degradation in solutions of alkali 
       3.3.2 Properties of the locally available formulation
             Insulin Injection
             This may be prepared by dissolving crystalline insulin 
             containing not less than 23 units/mg in water for 
             injections containing a suitable substance to render the 
             injection iso-osmotic with blood; hydrochloric acid to 
             adjust the pH to 3 to 3.5; and a suitable bactericide.  
             The USP specifies sterile, acidified or neutral solution 

             of insulin USP containing 40, 80, 100 or 500 units per 
             ml as well as 1.4 - 1.8% w/v of glycerol and 0.1 - 0.25% 
             (W/V) of phenol or cresol.
             pH of acidified injection 2.5 - 3.5
             pH of neutral injection 7 - 7.8
             Insulin injection is a colourless injection or straw 
             coloured liquid practically free from solid matter which 
             deposits on standing.  Contains not more than 40  g 
             zinc/100 units of insulin.  Sterilised by filtration and 
             kept in multidose containers.
             Neutral insulin BP
             Sterile buffered solution of bovine or porcine insulin 
             of potency not less than 23 units/mg;  pH 6.6 - 8 
             colourless liquid.  Contains not more than 20  g 
             zinc/100 units of insulin and a suitable bactericide.  
             Available in multidose containers.
             Insulin Zinc Suspension BP
             Sterile buffered suspension of mammalian insulin in the 
             form of a complex obtained by addition of zinc chloride. 
              Insulin is in a form insoluble in water.  Prepared by 
             mixing 3 volumes of insulin zinc suspension (amorphous) 
             and 7 volumes of insulin zinc suspension (crystalline).  
             Contains 40, 80, or 100 units/ml.  White suspension 
             available in multidose containers.  pH 6.9 - 7.5.  
             Complies with a test for prolongation of insulin effect.
             Insulin Zinc Suspension BP (Amorphous)
             Sterile buffered suspension of mammalian insulin in the 
             form of a complex obtained by addition of zinc chloride. 
              Prepared fromcrystalline insulin containing not less 
             than 23 u almost colourless suspension in which the 
             particles have no uniform shape and rarely exceed 2  m 
             in dimension; pH 6.9 - 7.5. Iso-osmotic with blood.  
             Containing suitable bactericide, the preparation 
             contains 40 and 80 units/ml.
             U.S.P. describes a sterile suspension of insulin U.S.P. 
             in buffered water for injection is modified by addition 
             of zinc chloride so that the solid phase of suspension 
             is amorphous.  Contains 40, 80 or 100 units/ml.
             Also contain sodium acetate 0.15 - 0.17%, sodium 
             chloride 0.65 - 0.75%, methyl hydroxy benzoate 0.09 - 
             0.11% and for each 100 units of insulin, 120 - 250  g of 
             zinc. pH 7.2-7.5
             Insulin zinc suspension (crystalline) BP

             Sterile buffered suspension of bovine insulin to which 
             zinc chloride is added.  Crystalline form is insoluble 
             in water.
             Prepared from crystalline insulin containing not more 
             than 23 units/mg.
             White or almost colourless suspension.  Particles are 
             mainly crystalline.  Majority of crystals having a 
             maximum diameter greater than 10  m.
             pH 6.9 - 7.5 Iso-osmotic with blood.  Preparation 
             contains 40 and 80 units/ml.
             U.S.P. - Sterile suspension of insulin contain 40, 80, 
             100 units/ml.  Contains sodium acetate, sodium chloride 
             and methyl hydroxybenzoate (Concentration same as for 
             amorphous insulin) and zinc 120 - 250 ug.  pH 7.2 - 7.5.
             Biphasic Insulin BP
             Sterile buffered suspension of crystals of bovine 
             insulin containing not less than 23 units/mg. in a 
             solution of porcine insulin of similar potency.  White 
             suspension.  pH 6.6 - 7.2 iso-osmotic with blood.  
             Contained 27.5 - 37.5 ug zinc for each 100 
             units/insulin.  Quarter of insulin in soluble form.  
             Multidose glass container.
             Globin zinc Insulin BP
             Sterile preparation of mammalian insulin in the form of 
             a complex obtained by addition of suitable globin and 
             zinc chloride.
             USP specification: Insulin modified by addition of zinc 
             and globin obtained from beef blood, 40, 80, 100 
             units/ml. Colourless liquid pH 3 - 3.8; iso-osmotic with 
             blood. Each 100 units of insulin also contains 3.6 - 4 
             mg of globin and 250 - 350  g zinc.
             USP specification: Also contains as preservatives phenol,
              glycerol and cresol.  Multidose container.
             Isophane Insulin
             Sterile buffered suspension of insulin in the form of a 
             complex obtained by addition of suitable protamine.  
             Prepared from crystalline insulin.
             pH 6.9 - 7.5 iso-osmotic with blood.
             Contains for each 100 units of insulin, 300 - 600  g 
             protamine sulphate and not more than 40  g zinc, a 
             suitable bactericide and sodium phosphate as buffering 

             USP specification: Sterile suspension of zinc insulin 
             crystalline and protamine sulphate in buffered water for 
             injection. Solid phase contain crystals of insulin 
             protamine and zinc; 40, 80, 100 units/ml.  Contains 
             glycerol, metacresol, phenol sodium phosphate and zinc.
             Protamine Zinc Insulin
             Sterile buffered suspension of mammalian insulin to 
             which protamine and zinc chloride are added.
             White suspension.  pH 6.9 - 7.5 iso-osmotic with blood.  
             Contains for each 100 units of insulin, 1 - 1.7 mg of 
             protamine sulphate and zinc chloride equivalent to 200 
             per  g of zinc, 10 - 11 mg of sodium phosphate.
             USP specification: Buffered sterile suspension to which 
             zinc chloride and protamine sulphate are added.  40, 80, 
             100 units/ml.  Also contain glycerol, cresol, phenol, 
             sodium phosphate for each 100 units of insulin in 
             addition to protamine and zinc.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             Up to 2 years at storage conditions of 2 - 8C
       3.4.2 Shelf-life of the locally available formulation
             Up to 2 years at storage conditions of 2 - 8C
       3.4.3 Storage conditions
             Store at 2 - 8C.  Avoid freezing.
       3.4.4 Bioavailability
             To be added by PCC using the monograph
       3.4.5 Specific properties and composition
             To be added by PCC using the monograph
    4. USES
     4.1 Indications
       (a)  Diabetes mellitus
       (b)  Complications of diabetes mellitus
            eg.  Hyperglycaemic ketoacidotic coma
                 Hyperglycaemic hyperosmolar non-ketotic coma
       (c)  Hyperkalaemia
       (d)  Insulin hypoglycaemia can be used as a test of anterior 
       pituitary function and to test completeness of vagotomy in 
       reducing gastric secretion.
     4.2 Therapeutic dosage
       4.2.1 Adults
             Blood sugar < 16.5 mmol/l (300 mg%): 20 units.
             Blood suger 11 - 16.5 mmol/l (200 - 300 mg%): 10 units.
       4.2.2 Children
             Dose is than adjusted according to the usual monitoring 
             of blood and/or urine glucose.  Daily dose increments 
             should be 4 units.  When stabilised, two-thirds of the 
             daily dose is generally given 30 minutes before 
             breakfast and one-third 30 minutes before the evening 

             If only one injection per day is required, 10 - 14 units 
             of an intermediate-acting insulin can be given.  Dose 
             increment is 4 units given on alternate days.  Soluble 
             or neutral may be added or special mixed insulins used 
             according to the patient's response.
     4.3 Contraindications
       Absolute  Hypoglycaemia
       Relative  Allergic reactions may occur to beef or porcine 
       Precautions:  Differing immunological response to bovine and 
       porcine insulin have been reported and hypoglycaemia has been 
       reported in patients changing from bovine to porcine insulin.  
       Care is recommended to avoid inadvertant change of insulin 
       from one species to another.  Care may be necessary in 
       changing over to a highly purified insulin.
       The hypoglycaemia caused by insulin may be enhanced by alcohol,
        monoamine oxidase inhibitors and propranolol and other beta 
       blockers.  Propranolol may mask the symptoms of hypoglycaemia.
       NB - Any deterioration in renal function and severe hepatic 
       disease may reduce insulin clearance and may result in 
     5.1 Oral
       When taken orally insulin has no hypoglycaemic effect since it 
       is inactivated in the gastrointestinal tract (Reynolds, 1982)
     5.2 Inhalation
       Not relevant
     5.3 Dermal
       Not relevant
     5.4 Eye
       Not relevant
     5.5 Parenteral
       Insulin is administered by subcutaneous, intramuscular or 
       intravenous injections and poisoning can occur only through 
       this route.
     5.6 Other
       Not relevant
     6.1 Absorption by route of exposure
       Insulin must be injected SC, IM or IV.  It is absorbed into 
       the blood and peak plasma insulin concentration with 
       subcutaneous insulin occurs at 60 - 90 min. Absorption is 
       slower if there is peripheral vascular disease or smoking, and 
       faster if the patient is vasodilated eg. by a hot bath or 
       ultraviolet exposure or exercise.
       Any changes in mode of administration either accidentally (eg. 
       accidental IM or IV injection) or deliberately (eg. constant 
       subcutaneous insulin infusion) may potentiate the absorption 
       and action of insulin, leading to hypoglycemia.  Severe 
       hypoglycaemia may occur during constant infusion and several 
       deaths have been reported (Paterson et al, 1983).

       Absorption of insulin from injection site affected by insulin 
       lipodystrophy is very unpredictable and rapid absorption may 
       lead to hypoglycaemia.
     6.2 Distribution by route of exposure
       A fraction of endogenous or exogenous insulin in plasma may be 
       associated with certain proteins but the bulk appears to 
       circulate in blood and lymph as the free hormone.  The volume 
       of distribution of insulin approximates the volume of 
       extrecellular fluid.
       Insulin is inactivated in the liver and kidneys (about 40% in 
       a single passage).  About 10% appear in the urine.
     6.3 Biological half-life by route of exposure
       The plasma half-life is:
       intravenous injection    10 minutes
       subcutaneous injection   4 hours
       intramuscular injection  2 hrs.
     6.4 Metabolism
       Metabolism occurs mainly in the liver and kidneys;  10% of the 
       dose appears in the urine.  Insulin is normally filtered at 
       the glomeruli and then completely reabsorbed or destroyed at 
       the proximal tubule.  In patients with impaired renal tubular 
       function, urinary clearance approaches glomerular filtration 
       rates.  50% of insulin that reaches the liver via the portal 
       vein is destroyed in a single passage, never reaching the 
       general circulation.  Proteolytic degradation of insulin 
       occurs both at cell surfaces and in the lysosomes.  A 
       proteolytic enzyme that degrades insulin has been purified 
       from muscle.  An enzyme, glutathione insulin transhydrogenase, 
       which utilises reduced glutathione to reduce disulfide bridges 
       of insulin and produce separate chains, has been implicated.
       Severe impairment of renal function appears to affect the rate 
       of disappearance of circulating insulin to a greater extent 
       than does hepatic disease.
     6.5 Elimination by route of exposure
       About 10% of the drug appears in urine.
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Insulin in overdose causes hypoglycaemia.  Hypoglycaemia 
             deprives the brain of substrate glucose upon which it is 
             almost exclusively dependent for its oxidative 
             metabolism.  During insulin coma, oxygen consumption in 
             the human brain decreases by nearly half.
             A prolonged period of hypoglycaemia causes irreversible 
             damage to the brain as evidenced in experimental animals 
             by histological changes in the cortex, basal ganglia and 
             rostral parts of the medulla.  Convulsions, coma, mental 
             retardation, hemiparesis, ataxia, incontinence, aphasia, 
             choreiform movements, and parkinsonism may occur in man.
       7.1.2 Pharmacodynamics
             Insulin binds to a receptor on the surface of the target 

             cell and probably also enters the cell in this state. 
             The receptors vary in number inversely with the insulin 
             concentration to which they are exposed.
             The receptor becomes phosphorylated on addition of 
             insulin and ATP. The cellular mechanism of action of 
             insulin after combination with the receptor is 
             uncertain;  the complex may activate a "second 
             messenger" which in turn causes the release of third 
             messenger Ca++ ions.  Insulin also has a membrane effect 
             in increasing gluose uptake and utilization, especially 
             by muscle and adipose tissue.  Its effects include the 
             a)   Reduction in blood sugar due to increased glucose 
             uptake in the peripheral tissues which convert it to 
             glycogen or fat, and reduction of hepatic output 
             (diminished breakdown of glycogen and diminished 
             gluconeogenesis).  When blood glucose falls below renal 
             threshold (180 mg/100 ml or 10 mmol/l) glycosuria ceases 
             as does the osmotic diuresis of water and electrolytes.  
             Polyuria and excessive thirst are thus alleviated.  If 
             blood glucose falls much below normal levels, appetite 
             is stimulated.
             b)   Other metabolic effects: Insulin stimulates the 
             transit of amino acids and potassium into the cells.  
             Insulin regulates utilization of carbohydrate and energy 
             products and enhances protein synthesis.
             c)   Insulin increases concentrations of the active form 
             of the enzyme pyruvate dehydrogenase.  Hence pyruvate is 
             oxidized or converted to fat and is unavailable for 
             glucose formation.  In addition to enhanced synthesis of 
             fat, insulin increases the activity of membrane bound 
             lipoprotein lipase which makes fatty acids derived from 
             circulating lipoproteins available to the cell.
     7.2 Toxicity
       7.2.1 Human data
                     In most normal adults, 0.1 - 0.2 Units/kg 
                     intravenously is sufficient to cause profound 
                     hypoglycaemia.  However, in insulin dependent 
                     diabetics, it is not possible to indicate the 
                     amount of insulin necessary to cause toxicity 
                     because the level of hypoglycaemia and its 
                     duration are the important factors.  For example,
                      patients who have taken 80 to 500 times of the 
                     normal dose taken for suicidal purposes have 
                     recovered (Martin et al, 1977).
                     No data available.
       7.2.2 Relevant animal data
             No data available.
       7.2.3 Relevant in vitro data
             No data available.

     7.3 Carcinogenicity
       Development of cancer at the site of long term insulin 
       injection has been reported.  (Eisenbad and Walter, 1975).
     7.4 Teratogenicity
       Congenital malformations occurred in 17 of 117 babies born to 
       diabetic mothers taking insulin at the time of conception (Pay 
       and Insley, 1976).
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Alcohol, beta blockers, salicylates, oxytetracycline and 
       monoamine oxidase inhibitors potentiate the hypoglycaemic 
       effects of insulin.  Bezafibrate and clofibrate may improve 
       glucose tolerance and have an additive effect. Corticosteroids,
        corticotrophin, diazoxide, diuretics like bumetanide, 
       furosemide and thiazides and oral contraceptives antagonise 
       the effects of insulin.  Lithium may occasionally impair 
       glucose tolerance.
     7.7 Main adverse effects
       (a)  Hypoglycaemia - symptoms are directly related to duration 
       and depth of hypoglycaemia.  Initial sympathetic overactivity 
       is followed by signs of neuroglycopenia.
       (b)  Non specific local reactions at site of injection eg. 
       pain, oedema.
       (c)  Allergic reactions
       (d)  Lipoatrophy or induration and hypertrophy at the site of 
       injection is asociated with chronic use.
       (e)  Insulin resistance.
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
    Toxicological analyses
                     Type of Plasma Insulin   a)   Bioassay
                                              b)   Immunoassay
                     Plasma insulin estimated by bioassay is called 
                     insulin-like activity (ILA) and plasma insulin 
                     estimated by immunoassay is called 
                     immunoreactive insulin (IRI); ILA and IRI differ 
                     qualitatively and quantitatively.  In vivo 
                     bioassays depend on lowering of blood glucose in 
                     rabbits or production of convulsions in mice.  
                     Several in vitro methods have become popular due 
                     to high degrees of sensitivity and relative 
                     simplicity of execution.  One method is based on 
                     the capacity of insulin to increase the glycogen 
                     content and glucose uptake of rat diaphragm.  
                     Adipose tissue assays are based on the capacity 
                     of insulin to stimulate glucose metabolism by 
                     the epididymal fat pad of the rat or by a 
                     suspension of isolated fat cells.

                     The sensitivity of radio-immunoassay is greater 
                     than that of other assays.
                     The following could be determined by radio-
                          a.   Total immunoreactive insulin (IRI)
                          b.   NEIRI - nonextracted immunoreactive 
                     plasma           insulin
                          c.   Free plasma insulin ('Free' IRI)
                          d.   I125 insulin binding in vitro
                          e.   Acute insulin sensitivity (KITT)
                          f.   Half-time of immunoreactive insulin    
                            disappearance (Gilman and Goodman, 1985; 
                     Martin et al,           1977).
                     Blood glucose estimation
                          Concentration of plasma IRI of normal 
                     persons after      an overnight fast is under 20 
    Biomedical analyses
    Arterial blood gas analysis
    Haematological analyses
    Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
    Toxicological analyses
    Biomedical analyses
    Arterial blood gas analysis
    Haematological analyses
    Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
    Toxicological analyses
    Biomedical analyses
    Arterial blood gas analysis
    Haematological analyses
    Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
    Simple Qualitative Test(s)
    Advanced Qualitative Confirmation Test(s)
    Simple Quantitative Method(s)
    Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
    Simple Qualitative Test(s)
    Advanced Qualitative Confirmation Test(s)
    Simple Quantitative Method(s)
    Advanced Quantitative Method(s)
    Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation

       8.3.1 Biochemical analysis
    Blood, plasma or serum
    Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
     9.1 Acute poisoning
       9.1.1 Ingestion
             Not relevant
       9.1.2 Inhalation
             Not relevant
       9.1.3 Skin exposure
             Not relevant
       9.1.4 Eye contact
             Not relevant
       9.1.5 Parenteral exposure
             0.4 units of monocomponent insulin injected 
             subcutaneously three times a day into each quadrant of a 
             pitted scar did not cause hypoglycaemia (Amroiwalla, 
             1977).  Insulin toxicity causes hypoglycaemic symptoms.
       9.1.6 Other
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Not relevant
       9.2.2 Inhalation
             Not relevant
       9.2.3 Skin exposure
             Not relevant
       9.2.4 Eye contact
             Not relevant
       9.2.5 Parenteral exposure
             Not relevant
       9.2.6 Other
             Not relevant
     9.3 Course, prognosis, cause of death
       Symptoms do not usually appear unless the blood glucose 
       concentration falls below 3.5 mmol/l.  Convulsions can occur 
       if the blood glucose concentration falls below 2 mmol/l.  Mild 
       hypoglycaemia is usually relieved rapidly by ingestion of 
       Even when the level of consciousness is impaired, parenteral 
       admiistration of glucose or glucagon will lead to full 
       recovery.  Sometimes brain damage is irreversible.
       Severe or prolonged neuroglycopenia may respond only slowly to 
       restoration of the plasma glucose concentration as concomitant 
       cerebral oedema may itself depress the level of consciousness. 
        Prolonged hypoglycaemia may cause irreversible cerebral 

       damage as manifested by chronically impaired cognitive 
       functions, convulsions and hemiparesis, eventually causing 
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute - Hypoglycaemia promotes the release of adrenalin 
             which causes palpitations and tachycardia.  When 
             hypoglycaemia is severe, angina, arrhythmias, premature 
             beats and coronary thrombosis may occur.
       9.4.2 Respiratory
             Shallow breathing is present in severe, prolonged 
             hypoglycaemic coma.
       9.4.3 Neurological
                     Signs of neuroglycopenia due to prolonged 
                     hypoglycaemia include intellectual impairment, 
                     irrational behaviour, blurring of vision, 
                     diplopia, headache, confusion, abnormal and 
                     often aggressive behaviour, mental retardation, 
                     hemiparesis, ataxia, incontinence, aphasia, 
                     choreiform movements, parkinsonism, epilepsy, 
                     convulsions, drowsiness and coma.
    Peripheral nervous system
                     Numbness of lips, nose or fingers.
    Autonomic nervous system
                     Initial sympathetic overactivity is observed due 
                     to hypoglycaemia as a result of the release of 
                     Symptoms include anxiety, hunger, sweating, 
                     weakness, pallor, palpitations and tremors.
    Skeletal and smooth muscle
       9.4.4 Gastrointestinal
             No data available.
       9.4.5 Hepatic
             No data available.
       9.4.6 Urinary
                     No data available.
                     Urinary incontinence.
       9.4.7 Endocrine and reproductive systems
             No data available.
       9.4.8 Dermatological
             Cutaneous bullae occur due to prolonged coma (similar to 
             those associated with barbiturate poisoning).
             Lipodystrophy - Fat atrophy and hypertrophy usually 
             occur with prolonged use of non purified insulins.
       9.4.9 Eye, ear, nose, throat: local effects
             Eye - Pupils are initially dilated and react to light.  
             Later pupils are constricted and cease to react to 
       9.4.10 Haematological
              Hypercoagulation has been reported.
       9.4.11 Immunological

              Immediate hypersensitivity: this occurs most frequently 
              during first few weeks of therapy.  Following an 
              injection a 'wheal and flare' response occurs around 
              injection site within 2 hours.  Local swelling is 
              maximal at 6 - 12 hrs but the reaction usually settles 
              within 24 - 48 hrs.
              Rarely, a widespread general hypersensitivity reaction 
              with widespread urticaria, gastrointestinal 
              disturbances and angioneurotic oedema will occur.
              Immediate hypersensitivity is mediated by IgE 
              Delayed hypersensitivity may occur shortly after 
              introducing insulin therapy.
              Erythema occurs around injection site 2 - 24 hrs after 
              injection and settles slowly over 2 - 3 days.  Rarely, 
              local residual scarring may occur.
              Type IV hypersensitivity is mediated by lymphocytes.
              These reactions subside spontaneously and are rarely 
              generalized but occasionally they may persist and 
              necessitate a change in insulin therapy. Most cases 
              occur with non-highly purified bovine insulin.
              Acute anaphylaxis to insulin is extremely rare.
       9.4.12 Metabolic
     Acid-base disturbances
                       Hypoglycaemic coma may lead to respiratory 
                       depression and anoxia with consequent 
     Fluid and electrolyte disturbances
                       Hyperinsulinaemia may itself cause 
                       hypokalaemia and hypoglycaemia provokes the 
                       release of adrenalin, which may also cause 
       9.4.13 Allergic reactions
              see 9.4.11.
       9.4.14 Other clinical effects
       9.4.15 Special risks
              Hypoglycaemia, severe in 17 cases, occurred during the 
              first 6 hours of life in 22 of 34 infants born to 
              diabetic mothers who received insulin.  Clinical 
              features were present only in two (Martin et al, 1975).
              Pregnancy: It is unclear whether insulin causes 
              congenital malformations, though diabetes certainly 
              does.  Neonatal hypoglycaemia is caused by neonatal 
              pancreatic hyperstimulation when diabetic mothers have 
              been hyperglycaemic.  Alcohol is an important risk 
              factor - and most cases of death from insulin have been 
              associated with alcohol.

     9.5 Other
       No data available.
     9.6 Summary
      10.1 General principles
         Correction of hypoglycaemia and the maintenance of normal 
         blood glucose concentration are the most important aspects 
         in management.  In conscious, cooperative patients, oral 
         therapy with a few lumps of sugar or glucose is adequate.
         Patients who have large subcutaneous depots of insulin 
         continue to absorb it over several days, and may need 
         glucose infusions.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Venous blood glucose concentration is measured on a 
                fresh sample taken into a tube containing fluoride-
                acetate.  A volume of 1-2 ml of whole blood is 
                sufficient.  If measurement is likely to be delayed, 
                the sample should be stored at 4C, though even at 
                this temperature there is some glucose consumption.  
                Where assay within a few hours is impossible, a 
                reliable result can be obtained by separating the 
                plasma and then freezing it at -20C.
                Diagnosis of hypoglycaemia is suggested by a low 
                glucose oxidase strip reading.
                Insulin assay is not helpful in patients with 
                antibodies, unless free insulin concentration can be 
         10.2.2 Biomedical analysis
                The blood glucose concentration should be measured.  
                Hypokalaemia can be detected by assay of serum 
         10.2.3 Toxicological analysis
                Refer to section 8.
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic/specific 
         If the patient is conscious and cooperative, give oral 
         glucose or sucrose (3-4 sugar lumps) and repeat after 15 
         minutes or earlier if symptoms recur.  This should be 
         supplemented by a carbohydrate meal until blood sugar is 
         If the patient is unconscious or uncooperative, give 50 ml 
         of 50% dextrose (25 g of glucose) IV.  If there is no 
         response within 15 minutes repeat the dose; glucagon 1 mg IM 
         or IV or SC is a less reliable alternative. This can also be 
         repeated but failure of the first glucagon injection is 
         unlikely to be followed by success with further doses.
         For children give approximately 1 ml/kg of 50% glucose and 
         repeat if there is no response.  A 10% glucose infusion via 

         a peripheral vein may be enough, but commonly 20% glucose 
         has to be given by the central vein.  
         If the patient is still unconscious despite this treatment 
         and blood sugar is normal or above normal then cerebral 
         oedema is likely and should be treated with 20% mannitol.  
         (Unless contraindicated due to cardiovascular disease).
         Blood glucose concentration should be measured every 15 - 30 
         minutes and the rate of infusion altered to keep the blood 
         glucose concentration within the range of 5 - 10 mmol/l.
         Give dexamethasone 10 mg IV followed by 16 mg daily in four 
         divided doses.  Give oxygen.
         Treatment with parenteral dextrose at doses up to 25 g/hr 
         may be necessary for protracted periods, depending on the 
         preparation of insulin injected.  Initially, 1% - 20% 
         solution via a large central vein may be necessary to 
         supplement oral carbohydrate ingestion.
         Occasionally neurological deficits recover after several 
         days if full supportive care is maintained.
         Frequent blood sugar estimations (venous or capillary) may 
         be necessary, particularly initially, according to the 
         clinical condition.  Plasma insulin estimations do not help 
         in the management.
         Treat hypokalaemia with potassium supplements.  Intravenous 
         potassium chloride 20 - 60 mEq per litre of fluid may be 
      10.4 Decontamination
         Not relevant
      10.5 Elimination
         Not relevant
      10.6 Antidote treatment
         10.6.1 Adults
                No specific antidotes are available
         10.6.2 Children
                No specific antidotes are available
      10.7 Management discussion
         Glucagon 1 mg IM is useful to correct hypoglycaemia.  
         However, there is a risk that glucagon-induced insulin 
         secretion may be a complication (Marri et al, 1968).
         Excision of the skin and fat of an insulin injection site 
         under a local anaesthetic has been performed in the 
         management of insulin overdose (McIntyre et al, 1986).
         Hypoglycaemia may develop later than predicted from the 
         duration of action of various insulin preparations (Haskell 
         and Stapezyriski, 1983).
      11.1 Case reports from literature
         Kaminer and Robbins (1988) reported a case of a 16 year old 

         girl with insulin-dependent diabetes mellitus who gave 
         herself an injection of 600 units of regular insulin in a 
         suicidal attempt.  She lost consciousness for 12 hours and 
         was found confused and disoriented.  She recovered fully.
         Martin et al (1977) reported a case of a young man with a 
         prior history of depressive illness who was found 
         unconscious about 12 hours after self-administration of 
         about 1,600 units of NPH insulin along with a large amount 
         of alcohol and barbiturates.  Despite the intravenous 
         administration of a large amount of glucose and 20% fructose 
         solution, hypoglycaemia recurred and his conscious state 
         deteriorated after an episode of respiratory obstruction.  
         He did not require further insulin for 6 days by which time 
         the blood glucose level had risen to 15 mmol/l.  Improvement 
         in his conscious state was slow and he had evidence of 
         marked mental impairment and emotional lability.
      11.2 Internally extracted data on cases
      11.3 Internal cases
    12. Additional information
      12.1 Availability of antidotes
      12.2 Specific preventive measures
         Patients should be advised regarding the correct dose and 
         injection technique. They should have an adequate knowledge 
         of early features of hypoglycaemia so that they can take 
         glucose or sugar immediately.
      12.3 Other
    Amroliwalla FK (1977). Br Med J 1: 1389 - 90
    British National Formulary (1988).  British Medical Association 
    and the Pharmaceutical Society of Great Britain.
    Dukes MNG (1988). Meyler's Side Effects of Drugs.  Amsterdam, 
    Elsevier Scientific Publishers.
    Eisenbad E, Walter RM (1975). J Am Med Ass 233: 985.
    Gilman AG, Goodman LS, Rall TW, Murad F (1985) ed. In: The 
    Pharmacological Basis of Therapeutics 7th Ed. Pergamon. p 1490 - 
    Haskell RJ, Stapezynski JS (1983).  Intravenous glucose for the 
    treatment of intentional insulin overdoses.  Ann Emerg Med 12: 
    Kaminer Y, Robbins DR (1988).  Attempted suicide by insulin 
    overdose in insulin-dependent diabetic adolescents.  Paediatrics 
    81: 526 - 528.
    Laurence DR, Bennett PN. Clinical Pharmacology. Churchill 
    Livingstone. Edinburgh.
    McIntyre AS, Woolf VJ, Burnhem WR (1986).  Local excision of 
    subcutaneous fat in the management of insulin overdose.  Br J 
    Surg 73: 538.

    Martin FIR, Hansen N, Warne GL (1977).  Attempted suicide by 
    insulin overdose in insulin-requiring diabetics.  Med J Austr 1: 
    Martin FIR et al (1975). Arch Dis Child 130: 998
    Paterson KR, Paice BJ, Lawson DH, (1983).  Undesired effects of 
    insulin therapy.  Adv Drug React Ac Pois Rev 2: 219-234
    Pay IR, Insley J (1976). Arch Dis Child 51: 935
    Reynolds JEF (1982) ed. Martindale, The Extra Pharmacopoeia. 28th 
    ed. The Pharmaceutical Press, London. p. 2025.
    Trevor M. Avery's Drug Treatment. 3rd ed.  ADIS Press. Auckland. 
    p. 530-535
    Author(s):Dr Ravindra Fernando 
              Dr (Mrs) Geetha Fernando 
              National Poisons Information Centre
              General Hospital
              Colombo 8
              Sri Lanka
              Tel: 94-1-94016
              Fax: 94-1-599231
    Date:     April 1990
    Reviewer: Dr R. Ferner
              West Midlands Poisons Unit
              Dudley Road Hospital
              Birmingham B18 7QH
              United Kingdom
              Tel: 44-21-5543801
              Fax: 44-21-5236526
    Date:     February 1991
    Peer review: Adelaide, Australia, April 1991

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    This report contains the collective views of an international group of

    experts and does not necessarily represent the decisions or the stated

    policy of the United Nations Environment Programme, the International

    Labour Organisation, or the World Health Organization.


    Published under the joint sponsorship of

    the United Nations Environment Programme,

    the International Labour Organisation,

    and the World Health Organization


    World Health Orgnization

    Geneva, 1988

         The International Programme on Chemical Safety (IPCS) is a

    joint venture of the United Nations Environment Programme, the

    International Labour Organisation, and the World Health

    Organization. The main objective of the IPCS is to carry out and

    disseminate evaluations of the effects of chemicals on human health

    and the quality of the environment. Supporting activities include

    the development of epidemiological, experimental laboratory, and

    risk-assessment methods that could produce internationally

    comparable results, and the development of manpower in the field of

    toxicology. Other activities carried out by the IPCS include the

    development of know-how for coping with chemical accidents,

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        ISBN 92 4 154261 6  


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    1.1. Summary

         1.1.1. Analytical methods

         1.1.2. Sources of chromium, environmental levels and exposure

         1.1.3. Metabolism

         1.1.4. Effects on experimental animals

         1.1.5. Effects on human beings

        Clinical and epidemiological studies

         1.1.6. Evaluation of risks for human health

    1.2. Recommendations for further research

         1.2.1. Analytical methods

         1.2.2. Sources of chromium intake

         1.2.3. Studies on health effects

         1.2.4. Interaction with other environmental factors




    2.1. Physical and chemical properties

    2.2. Analytical methods

         2.2.1. Sampling

         2.2.2. Analytical methods




    3.1. Natural occurrence

         3.1.1. Rocks

         3.1.2. Soils

         3.1.3. Water

         3.1.4. Air

         3.1.5. Plants and wildlife

         3.1.6. Environmental contamination from natural sources

    3.2. Production, consumption, and uses

    3.3. Waste disposal

    3.4. Miscellaneous sources of pollution

    3.5. Environmental transport and distribution




    4.1. Environmental levels

         4.1.1. Air

         4.1.2. Water

         4.1.3. Food

    4.2. General population exposure

         4.2.1. Food and water

         4.2.2. Other exposures

    4.3. Occupational exposure

         4.3.1. Inhalation exposure

         4.3.2. Dermal exposure




    5.1. Absorption

         5.1.1. Absorption through inhalation

        Animal studies

        Human data

         5.1.2. Absorption from the gastrointestinal tract

        Animal studies

        Human data

    5.2. Distribution, retention, excretion

         5.2.1. Animal studies

         5.2.2. Human data

        Concentration in tissues, blood, urine,

                         and hair including possible biological

                         indicators of exposure

        Dynamic aspects of metabolism

                         and the influence of pathological states

    5.3. Influence of chemical form




    6.1. Microorganisms

    6.2. Plants

    6.3. Aquatic organisms




    7.1. Nutritional effects of chromium

         7.1.1. Effects of deficiency on glucose metabolism

         7.1.2. Effects of deficiency on lipid  metabolism

         7.1.3. Effects of deficiency on life span, growth, and reproduction

         7.1.4. Other effects of deficiency

         7.1.5. Mechanism of action of chromium as an essential nutrient

        Enzymes, nucleic acids, and thyroid

        Interaction of chromium with insulin

         7.1.6. Chromium nutritional requirements of animals

     7.2. Toxicity studies

         7.2.1. Effects on experimental animals



        Developmental toxicity and other

                         reproductive effects

        Cytotoxicity and micromolecular syntheses


         7.2.2. Observations in farm animals




    8.1. Nutritional role of chromium

         8.1.1. Biological measurements and their interpretation

         8.1.2. Chromium deficiency


        Malnourished children

        Patients on total parenteral alimentation

        Epidemiological studies


         8.1.3. Mode of action

    8.2. Acute toxic effects

    8.3. Chronic toxic effects

         8.3.1. Effects on skin and mucous membranes

        Primary irritation of the skin

                         and mucous membranes

        Allergic contact dermatoses

         8.3.2. Effects on the lung

        Bronchial irritation and sensitization

         8.3.3. Effects on the kidney

         8.3.4. Effects on the liver

         8.3.5. Effects on the gastrointestinal tract

         8.3.6. Effects on the circulatory system

         8.3.7. Teratogenicity

         8.3.8. Mutagenicity and other short-term tests

         8.3.9. Carcinogenicity

        Lung cancer

        Cancer in organs other than lungs

        Relative risk between cancer risk

                         and chromium compound




    9.1. Occupational exposure

         9.1.1. Effects other than cancer

        Respiratory tract



        Other organs and systems

         9.1.2. Teratogenicity

    9.2. General population








Professor Chen Bingheng, Department of Environmental Health,

   Shanghai Medical University, Shanghai, China


Dr H.N.B. Gopalan, University of Nairobi, Department of Botany,

   Nairobi, Kenya


Professor C.R. Krishna Murti, Integrated Environmental 

   Programme on Heavy Metals, Department of Environment,

   Government of India, New Delhi, India  (Vice-Chairman)


Professor Aly Massoud, Department of Community, Environmental

   and Occupational Medicine, Faculty of Medicine, Ain Shams

   University, Cairo, Egypt


Dr W. Mertz, Human Nutrition Research Center, US Department of

   Agriculture, Beltsville, Maryland, USA  (Chairman)


Professor I.V. Sanotsky, Department of Toxicology, Institute

   of Industrial Hygiene and Occupational Diseases, Academy

   of Medical Sciences of the USSR, Moscow, USSR


Professor W. Stöber, Fraunhofer Institute for Toxicology and

   Aerosol Research, Hanover, Federal Republic of Germany




Dr J. Parizek, International Programme on Chemical Safety,

   World Health Organization, Geneva, Switzerland  (Secretary)


Dr R.F. Hertel, Fraunhofer Institute for Toxicology and

   Aerosol Research, Hanover, Federal Republic of Germany

    (Temporary Adviser) (Rapporteur)


Dr T. Ng, Office of Occupational Health, World Health

   Organization, Geneva, Switzerland


Mr J.D. Wilbourn, Unit of Carcinogen Identification and

   Evaluation, International Agency for Research on Cancer,

   Lyons, France



    Every effort has been made to present information in the

criteria documents as accurately as possible without unduly

delaying their publication.  In the interest of all users of the 

environmental health criteria documents, readers are kindly 

requested to communicate any errors that may have occurred to the 

Manager of the International Programme on Chemical Safety, World 

Health Organization, Geneva, Switzerland, in order that they may be 

included in corrigenda, which will appear in subsequent volumes. 

                       *    * *

    A detailed data profile and a legal file can be obtained from 

the International Register of Potentially Toxic Chemicals, Palais 

des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 - 




    A WHO Task Group on Environmental Health Criteria for Chromium 

met in Geneva from 24 to 27 March 1986. Dr J. Parizek opened the 

meeting on behalf of the Director-General.  The Task Group reviewed 

and revised the draft criteria document and made an evaluation of 

the health risks of exposure to chromium. 


    The initial draft was prepared by the INSTITUTE FOR GENERAL AND 

COMMUNITY HYGIENE, MOSCOW.  The second draft criteria document was 





Republic of Germany. 


    The efforts of all who helped in the preparation and 

finalization of the document are gratefully acknowledged. 

                         * * *

    Partial financial support for the publication of this criteria 

document was kindly provided by the United States Department of 

Health and Human Services, through a contract from the National 

Institute of Environmental Health Sciences, Research Triangle Park, 

North Carolina, USA - a WHO Collaborating Centre for Environmental 

Health Effects.  The United Kingdom Department of Health and Social 

Security generously supported the cost of printing. 



1.1.  Summary


1.1.1.  Analytical methods


    Many analytical methods are available for the determination of 

chromium at trace levels, often in the 0.001 mg/kg range.  Among 

these are flameless atomic absorption spectrometry, atomic emission 

spectrometry with various excitation sources (the inductively-

coupled plasma torch is particularly advantageous), gas 

chromatography, destructive or non-destructive neutron activation 

analysis, and mass spectrometry using double-isotope dilution.  

Depending on the particular sample under examination as well as the 

analytical technique selected for the determination, wet or dry 

ashing procedures may be necessary to destroy the organic/inorganic 

matrix and minimize interelemental effects. 


    Determination of very low chromium concentrations in 

"unexposed" biological material (animal and human tissues, blood, 

urine, food, as well as water and air) is extremely difficult and 

many problems still have to be solved.  An accurate assessment of 

human exposure and nutritional chromium requirements depends on 

reliable analytical results. Chromium concentrations in blood, 

urine, and some low-chromium foods are close to or less than 1 

µg/kg, which is near the detection limit of even the most sensitive 

analytical methods.  Thus, agreement as to "normal" levels of 

chromium among analytical investigators has been poor, and results 

of interlaboratory comparisons have differed widely, usually by one 

order of magnitude. Only in recent years has agreement been reached 

that "normal" chromium concentrations in unexposed blood and urine 

are in the range of 0.1 - 0.5 µg/litre.  In this concentration 

range, it is not only the sensitivity of the final determination 

step that is limiting.  The preceding steps of sample collection, 

preparation, and digestion are equally important.  Contamination, 

easily introduced through cutting instruments and dust during 

collection, must be carefully controlled.  Digestion procedures are 

of the greatest importance.  Too rigorous treatment by heat or 

certain acids can cause a loss of chromium.  Few biological 

standard reference materials, certified for chromium, are available 

and almost all of the older, and most of the recent, published data 

were not checked using certified standards. For this reason, 

quantitative data concerning chromium concentrations in the range 

of < 1 - 100 µg/kg in biological materials must be considered 

uncertain, and caution must be used in interpreting their health-

related significance. 


    Differential analysis for chromium species is of great 

scientific and public health concern, in view of the substantial 

differences in the biological availability and in the toxicity of 

hexavalent chromium (Cr VI) compared with trivalent (Cr III).  

Though methods based on solvent extraction, with or without prior 

oxidation, differentiate between these two oxidation states, few 

analytical data contain this important information. 


    The understanding of the chemical and physical principles of 

chromium determination is increasing, and existing methods are 

being improved and new methods developed.  However, at present, 

analysis for chromium is a sophisticated procedure requiring the 

full attention of a highly trained analytical chemist. 


1.1.2.  Sources of chromium, environmental levels and exposure


    Chromium occurs ubiquitously in nature (< 0.1 µg/m3 in air).  

Natural levels in uncontaminated waters range from fractions of 1 

µg to a few µg/litre. 


    The concentration of chromium in rocks varies from an average 

of 5 mg/kg (granitic rocks) to 1800 mg/kg (ultramafic/basic and 

serpentine rocks).  The earth's most important deposits are either 

in the elemental or the trivalent oxidation state. 


    In most soils, chromium occurs in low concentrations (2 - 60 

mg/kg), but values of up to 4 g/kg have been reported in some 

uncontaminated soils.  Only a fraction of this chromium is 

available to plants.  It is not known whether chromium is an 

essential nutrient for plants, but all plants contain the element 

(up to 0.19 mg/kg on a  wet weight basis). 


    Almost all the hexavalent chromium in the environment arises 

from human activities.  It is derived from the industrial oxidation 

of mined chromium deposits and possibly from the combustion of 

fossil fuels, wood, paper, etc.  In this oxidation state, chromium 

is relatively stable in air and pure water, but it is reduced to 

the trivalent state, when it comes into contact with organic matter 

in biota, soil, and water.  There is an environmental cycle for 

chromium, from rocks and soils to water, biota, air, and back to 

the soil. However, a substantial amount (estimated at 6.7 x 106 kg 

per year) is diverted from this cycle by discharge into streams, 

and by runoff and dumping into the sea.  The ultimate repository is 

ocean sediment. 


    Chromium compounds are used in ferrochrome production, 

electroplating, pigment production, and tanning.  These industries, 

the burning of fossil fuels, and waste incineration are sources of 

chromium in air and water.  Most of the liquid effluent from the 

chromium industries is trapped and disposed of in land fills and 

sewage sludges, the chromium being in the form of the insoluble 

trivalent hydroxide. 


    In chromium ore mines, the concentration of chromium in dust 

ranges from 1.3 to 16.9 mg/m3.  During the production of refined 

ferrochromium, the air in the work-place may contain large amounts 

of dust (0.03 - 3.2 mg/m3).  In chromium plating factories, 

concentrations of 1 µg/m3 up to 1.4 mg/m3 have been measured.  In 

Portland cement from 9 European countries, the contents of chromium 

(VI), extractable with sodium sulfate, varied from 1 to 83 g/kg 



    Today, it is generally accepted that only the zero-, di-, tri-, 

and hexavalent oxidation states have biological importance.  The 

effects of the last 2 oxidation states are so fundamentally 

different that they must always be considered separately.  The 

trivalent form is an essential nutrient for man, in amounts of 50 - 

200 µg/day. 


1.1.3.  Metabolism


    The kinetics of chromium depend on its oxidation state and the 

chemical and physical form within the oxidation state. Most of the 

daily chromium intake (50 - 200 µg) is ingested with food and is in 

the trivalent form.  About 0.5 - 3% of the total intake of 

trivalent chromium is absorbed in the body. It is possible, but it 

has not yet been proved, that chromium in the form of some 

complexes, such as a dinicotinic-acid-complex, glucose tolerance 

factor, is better available for absorption.  The gastrointestinal 

absorption of 3 - 6% of the total intake of hexavalent chromium has 

been reported.  Once absorbed, chromium is almost entirely excreted 

with the urine; the daily urinary-chromium loss of 0.5 - 1.5 µg is 

approximately equal to the amount absorbed from the average diet.  

However, dermal losses, losses by desquamation of intestinal cells 

and by perspiration have not been quantified.  Ingested or injected 

chromium leaves the blood rapidly.  Blood-chromium levels do not 

reflect the overall chromium content of tissues, except after a 

glucose load, which induces an immediate increase in the plasma- 

and urine-chromium levels of chromium-sufficient subjects. 

Trivalent chromium inhaled from the air is trapped in the lung 

tissues, if in the form of small particles within the respirable 

range.  The chromium concentrations in lungs increases with age.  

Larger particles (greater than 5 µm), regardless of oxidation 

state, are moved to the larynx by ciliary action and become part of 

the dietary intake. 


    The intestinal absorption of hexavalent chromium is 3 - 5 times 

greater than that of trivalent forms; however, some of it is 

reduced by gastric juice.  Soluble chromates are rapidly absorbed 

through the epithelium of the alveoli and bronchi and cleared into 

the circulation, where part is preferentially accumulated by the 

red cells and part is excreted by the kidneys.  With the exception 

of the lungs, tissue levels of chromium decline with age. 


1.1.4.  Effects on experimental animal


    Doses of hexavalent chromium greater than 10 mg/kg diet affect 

mainly the gastrointestinal tract, kidneys, and probably the 

haematopoetic system.  When a similar dose is introduced 

parenterally, the principal effect is on the kidney, mainly in the 

proximal convoluted tubules, without evidence of glomerular damage.  

Toxic effects from trivalent chromium have been reported only 

following parenteral administration.  Dietary toxicity has not been 

reported, even in studies on cats administered amounts of up to 1 

g/day for 1 - 3 months.  When intravenously injected in mice, the 

LD50 of chromium carbonyl was 30 mg/kg body weight; this represents 

a 10 000-fold excess over the therapeutic dose required to cure 

signs of chromium deficiency. 


    Many studies on experimental animals have been conducted with 

chromium compounds in efforts to reproduce cancer similar to that 

found in man, when exposed to chromium. 


    Most tests have involved subcutaneous, intramuscular, or 

intrapleural injection.  In addition, several hexavalent chromium 

compounds have been administered to rats by intrabronchial 

implantation or intratracheal instillation. Relatively insoluble 

compounds, calcium chromate, strontium chromate, and certain forms 

of zinc chromate produced bronchogenic carcinomas; lead chromate, 

and barium chromate produced weak responses.  Intratracheal 

instillation of soluble sodium dichromate and dissolved calcium 

chromate produced bronchogenic tumours.  Injection of lead 

chromate, lead chromate oxide, and cobalt-chromium alloy resulted 

in the production of local sarcomas.  Thus, there is sufficient 

evidence that certain hexavalent chromium compounds are 

carcinogenic for experimental animals.  No increased tumour 

incidence was observed when trivalent compounds were given orally; 

however, the doses administered were low. 


    Hexavalent chromium has been reported to cause various forms of 

genetic damage in short-term mutagenicity tests, including damage 

to DNA, and misincoporation of nucleotides in DNA transcription.  

It was mutagenic in bacteria in the absence of an exogenous 

metabolic activation system, and in fungi.  Hexavalent chromium was 

also mutagenic in mammalian cells  in vitro and in vivo.  

Hexavalent chromium caused chromosomal abererations and sister 

chromatid exchanges in mamalian cells  in vitro. A few positive 

results in  in vitro assays for mammalian cell chromosomal 

aberrations and sister chromatid exchanges were obtained only with 

very high doses and could be explained by nonspecific toxic 

effects.  It induced formation of micronuclei in mice  in vivo.  

Potassium dichromate induced dominant lethal mutations in mice 

treated  in vivo. 


    Trivalent chromium is genetically active only in  in vitro

tests, where it can have a direct interaction with DNA, e.g., in 

experiments using purified DNA or tests to measure decreased 

fidelity of DNA synthesis  in vitro. Reduction of chromium (VI) 

within the cell nucleus and the formation of chromium (III) 

complexes suggests that chromium (III) would be the ultimate 

mutagenic form of chromium.  Trivalent chromium was present in RNAs 

from all sources examined and probably contributes to the stability 

of the structure.  Injected chromium trichloride (CrCl3) 

accumulated in the cell nucleus (up to 20% of cellular chromium 

content).  It enhanced RNA synthesis in mice and in regenerating 

rat liver, suggesting that chromium (III) is involved directly in 

RNA synthesis.  On the other hand, chromium (VI) inhibited RNA 

synthesis and DNA replication in several systems. 


1.1.5.  Effects on human beings


    Studies on man and experimental animals have established the 

essential role of trivalent chromium for the maintenance of normal 

glucose metabolism.  Chromium deficiency has been demonstrated in 


malnourished children, in two patients on total parenteral 

nutrition, and in middle-aged subjects, the basic disturbance being 

an impairment of the action of circulating insulin.  Clinical and epidemiological studies


    In adult human subjects, the lethal oral dose is 50 - 70 mg 

soluble chromates/kg body weight.  The most important clinical 

features produced following this route of entry are liver and 

kidney necrosis and poisoning of blood-forming organs. 


    Hexavalent chromium causes marked irritation of the respiratory 

tract.  Ulceration and perforation of the nasal septum have 

occurred frequently in workers employed in the chromate producing 

and hexavalent chromium-using industries. In addition to 

inhalation, direct contact of the nasal septum with contaminated 

hands contributes to nasal exposure.  Cancer of the septum has not 

been reported.  Rhinitis, bronchospasm, and pneumonia may result 

from exposure to hexavalent compounds together with impairment of 

pneumodynamics during respiration. 


    Chromate compounds, mainly sodium and potassium chromate and 

dichromate, cause irritation of the skin and ulcers may develop at 

the site of skin damage.  Exposure to trivalent chromium does not 

produce such effects.  Certain persons manifest allergic skin 

reactions to hexavalent and possibly trivalent chromium.  Skin 

reactions through dermal exposure to chromium are often described, 

chromate being the most common contact allergen.  However, cancer 

of the skin due to chromium exposure has not been reported. 


    Chronic effects of exposure to chromium (excessive industrial 

exposure of the skin to hexavalent chromium, when associated with 

damaged skin or inhalation of airborne chromium (VI) or mixed dust) 

occur in the lung, liver, kidney, gastrointestinal tract, and 

ciculatory system.  Teratogenic risks from chromium exposure have 

not been reported for human subjects; a mutagenic potency is shown 

for potassium dichromate and therefore cannot be excluded for 

chromates in the chromate-using industries. 


    The results of epidemiological studies in various countries 

have demonstrated that men working in chromate-production plants 

before 1950 had a very high rate of bronchogenic carcinoma, 

compared with control populations. Because of the long period 

between initial exposure and the detection of cancer and the lack 

of data on the extent and type of exposure, the dose-response 

relationship has not been quantified.  However, the few data 

available indicate that, before the danger of cancer was 

recognized, the exposure levels in such plants were very high.  

Recent data show clearly that, though the risk of cancer in workers 

in modern plants has been greatly reduced, it still remains a 



    Some epidemiological data suggest that an excess of lung cancer 

has also occurred in the chromate-pigment industry.  A few cases of 

cancer involving the upper respiratory tract have been reported, 

but cancer has not been convincingly demonstrated in other body 


tissues.  The specific compounds responsible for the cancers have 

not been identified.  Both hexavalent and trivalent compounds were 

present in the old plants.  However, on the basis of experimental 

animal studies, it is currently assumed that the slowly soluble, 

hexavalent chemicals, such as calcium and zinc chromate are 

responsible for the cancers.  This is based on the theory that 

these compounds remain in contact with the tissues for long periods 

of time (depot effect). 


    Trivalent chromium is not considered to be carcinogenic for the 

following reasons: (a) there was no evidence of excess cancer in 

studies in two industries where only trivalent compounds were 

present; (b) results of experimental animal and mutagenicity 

studies with trivalent chromium, were negative; and (c) because of 

the chemical and biological characteristics of the trivalent state, 

i.e., non-oxidizing, non-irritating, and probably unable to 

penetrate cell membranes. 


1.1.6.  Evaluation of risks for human health


    Chromium in the form of trivalent compounds is an essential 

nutrient.  The daily human intake of chromium varies considerably 

between regions.  Typical values range from 50 to 200 µg/day.  Such 

intakes do not represent a toxicity problem, and they coincide with 

the calculated human requirements.  Not enough data are available 

for a quantitative assessment of the risk of chromium deficiency in 

different populations. 


    Evidence from studies on experimental animals shows that 

hexavalent chromium compounds, especially those of low solubility 

can induce lung cancer.  Mutagenicity and related studies have 

shown convincingly that hexavalent chromium is genetically active.  

On the other hand, trivalent chromium compounds are  inactive in 

most test systems, except in systems where they can directly 

interact with DNA. 


    Both oxidation states, when injected at high levels 

parenterally in animals, are teratogenic, with the hexavalent form 

accumulating in the embryos to a much greater extent than the 



    A number of effects can result from occupational exposure to 

airborne chromium, including irritative lesions of the skin and 

upper respiratory tract, allergic reactions, and cancers of the 

respiratory tract.  The data on other effects in, e.g., the 

gastrointestinal, cardiovascular, and urogenital systems are 

insufficient for evaluation. 


    Epidemiological studies have shown that workers engaged in the 

production of chromate salts and chromate pigments are at increased 

risk of developing bronchial carcinoma.  No detailed data on dose-

response relationships are available.  Although a suspicion of 

increased lung cancer risks in chromium-plating workers has been 

raised, the available data are inconclusive and so are data for 

other industrial processes where chromium compounds are used rather 


than produced.  There is insufficient evidence to implicate 

chromium as a causative agent of cancer in any organ other than the 

lung.  The frequency of sister chromatid exchanges in the 

lymphocytes of workers in chromium-plating factories was higher 

than in control groups. 


    The general population living in the vicinity of ferro-alloy 

plants and exposed to ambient air concentrations of up to 1 µg/m3 

did not show increased lung cancer mortality. 


    The results of many studies suggest that exposure to chromium 

through inhalation and skin contact can pose health problems for 

the general population, but no data on dose-response relationships 

are available.  Thus, there is no reason, at present, to be 

concerned that chromium in the air presents a health problem, 

except under conditions of industrial exposure. 


1.2.  Recommendations for Further Research


1.2.1.  Analytical methods


    Data from the determination of chromium should not be accepted 

unless proper quality assurance procedures have been used, 

including the analysis of a certified reference material of similar 

composition.  There is a great need for the preparation and 

certification of additional standards, especially of blood, serum, 

or plasma, urine containing only physiological chromium 

concentrations, hair, and foods. 


    All analyses related to the environmental role of chromium 

should differentiate between hexavalent and trivalent forms and 

these values should be reported separately.  While the 

differentiation between hexavalent and trivalent chromium can be 

accomplished by established methods, the definition of the exact 

chemical species of the trivalent and hexavalent forms in air, 

water, food, and tissues will require much further research. 


    Further development of analytical instrumentation and 

preanalytical processing techniques to extend the detection limit 

by one order of magnitude is recommended.  The need for 

interlaboratory comparison persists to improve existing methods and 

to validate new procedures. 


1.2.2.  Sources of chromium intake


    More data are needed on the chemical and physical properties of 

airborne chromium, such as the oxidation state, particle size, and 

solubility.  These are important determinants of biological and 

toxic action.  Existing information on the chromium contents of 

foodstuffs is unreliable and incomplete and more composition data 

are needed for a valid assessment of the human chromium requirement 

and the supplies available in different regions of the world to 

meet these requirements.  Diagnostic procedures to detect marginal 

deficiency and marginal overexposure in man must be developed and 

the long-term effects of both these imbalances must be defined.  


Finally, not enough is known about the fate of chromium in 

landfills, sewage sludges, and aquatic environments.  Further 

studies are needed to investigate environmental factors that 

influence the mobilization, migration, and bioavailability of 

chromium in the biosphere. 


1.2.3.  Studies on health effects


    Prospective studies on the health of industrial workers, 

combined with the determination of the composition and 

environmental levels of the chromium compounds to which they were 

exposed, are needed to determine the specific chemical or chemicals 

responsible for cancer, and the dose-response relationship between 

hexavalent chromium and bronchogenic carcinoma.  Smoking histories 

should be recorded and, when possible, information on exposure to 

ionizing radiation and other chemical carcinogens should be 

obtained in order to evaluate possible synergistic relationships.  

More studies should be carried out on the chrome-using industries. 

Preventive measures include searching for more specific biochemical 

indicators of chromium exposure and early effects. 


    Epidemiological studies are needed to assess the incidence and 

severity of chromium deficiency.  The relation of chromium status 

to cardiovascular diseases needs further investigation, 

particularly in areas with protein-energy malnutrition. 


1.2.4.  Interaction with other environmental factors


    The interaction of other pollutants in the atmosphere with 

chromium, particularly with respect to particle size, adsorption at 

the particle surface, etc., require further studies. 


    Interactions between trivalent chromium in the diet and other 

dietary constituents are poorly understood and should be 





2.1.  Physical and Chemical Properties


    Chromium (atomic number 24, relative atomic mass 51.996) occurs 

in each of the oxidation states from -2 to +6, but only the 0 

(elemental), +2, +3, and +6 states are common.  Divalent chromium 

is unstable in most compounds, as it is easily oxidized to the 

trivalent form by air.  Only the trivalent and hexavalent oxidation 

states are important for human health. In the context of this 

publication, it is of great importance to realize that these two 

oxidation states have very different properties and biological 

effects on living organisms, including man.  Therefore, they must 

always be examined separately: a valid generalization of the 

biological effects of chromium as an element cannot be made. 


    This discussion will concentrate only on the aspects of 

chromium chemistry that are of concern for health. 


    The relation between the hexavalent and trivalent states of 

chromium is described by the equation: 


    Cr2O72- + 14H+ + 6e  -> 2 Cr(III) + 7H2O + 1.33v.


The difference electric potential between these 2 states reflects 

the strong oxidizing properties of hexavalent chromium and the 

substantial energy needed to oxidize the trivalent to the 

hexavalent form.  For practical purposes, it can be stated that 

this oxidation never occurs in biological systems.  The reduction 

of hexavalent chromium occurs spontaneously in the organism, unless 

present in an insoluble form.  A gradual reduction of hexavalent 

chromium to the trivalent state is demonstrated by the colour 

change of the conventional chromate cleaning solution in the 

laboratory from bright orange to green, in the presence of organic 

matter.  In blood, chromate is reduced to the trivalent state, once 

it has penetrated the red cell membrane and becomes bound to the 

haemoglobin and other constituents of the cell and therefore unable 

to leave the cell again.  The rapid reduction of injected 

51chromium-labelled chromate in the rat has been demonstrated by 

Feldman (1968).  Although a compound CrF6 is well known, the stable 

forms of hexavalent chromium are almost always bound to oxygen 

(e.g., CrO4-2, Cr2O7-2).  The trivalent form exists in coordination 

compounds, but never as the free ion.  As a rule, its coordination 

number is 6, the complexes being generally octahedral. 


    A large number of complexes and chelates of chromium have been 

investigated, ranging from simple hexa- or tetra-aquo complexes to 

those with organic acids, vitamins, amino acids and others.  The 

rate of ligand exchange of chromium complexes is slow in comparison 

with other transition elements, with the exception of the even 

slower rate of cobalt complexes; most of the Cr(III)-complexes are 

kinetically stable in solutions.  This property adds to the relative 

inertness of trivalent compounds, in addition to the 

electrochemical stability of the trivalent state.  However, at near 

neutral or alkaline pH, the milieu of the animal organism, the 


simple chromium compounds to which the organism is exposed in the 

environment or through supplementation, rapidly become insoluble, 

because hydroxyl ions replace the coordinated water molecules from 

the metal and form bridges, linking the chromium atoms into very 

large, insoluble complexes.  Coordination of trivalent chromium to 

biological ligands is the prerequisite for its solubility at 

physiological pH and therefore for its biological function and for 

its availability for intestinal absorption.  The coordination 

chemistry and the specific biochemical reactions have been reviewed 

by Cotton & Wilkinson (1966) and Mertz (1969), respectively.  The 

physical and chemical properties of chromium and some chromium-

compounds are summarized in Table 1. 


Common chromium compounds


    Poorly soluble "sandwich complexes" of metallic chromium 

(oxidation state = O) are known, e.g., Cr(C6H6)2; these have little 

practical application.  Divalent compounds, such as chromium (II) 

chloride (CrCl2) are used as strong reducing agents in the 

laboratory, but have little industrial use.  Of the many hundreds 

of trivalent chromium compounds known, chromic oxide (Cr2O3 x 

nH2O), is used as a pigment in paints and as a faecal marker in 

digestive studies.  It dissolves in acids and forms the hexa-aquo 

or tetra-aquo complex, e.g., 


    Cr2O3 x 9H2O + 6HCl  -> 2 [Cr(H2O)6] Cl3

                    (colour: violet)


           2 [Cr(H2O)4Cl2] Cl + 4H2O

                  (colour: dark green).


Chromium chloride ([Cr(H2O)6]Cl3 or [Cr(H2O)4Cl2]Cl) is used in 

basic solution for leather tanning.  The fluoride is used 

industrially in printing and dyeing, and chromium sulfates and 

nitrates are used as colouring and printing dyes. 


    One of the numerous organic complexes of chromium, a 

dinicotinatoglutathionato-chromium complex has been isolated from 

yeast.  It is postulated as the physiologically active form in the 

animal organism, but its exact structure is not known (Toepfer et 

al., 1977). 

Table 1.  Physical and chemical properties of chromium and some selected chromium compounds


Name             Chemical Relative   Specific Melting Boiling   Colour Solubility CAS registry

                 symbol    molecular gravity   point point         in water number

                           mass       (g/cm3) (°C)       (°C) (weight %)


Chromium         Cr 51.996     7.19 1857 2672      steel- insoluble 7440-47-3



Chromium (III)-  Cr2O3 151.99     5.21 2266 4000      green insoluble 1308-38-9



Chromium (VI)-   CrO3 99.99     2.70 196 decompo-  red 62.41 1333-82-0

oxide                                                      sition


Potassium-       K2CrO4 194.20     2.732 968.3 decompo-  yellow 39.96 7789-00-6

chromate (VI)                                              sition


Potassium-       K2Cr2O7 294.19     2.676 398 decompo-  red 11.7 7778-50-9

dichromate (VI)                                            sition


Calcium-         CaCrO4 192.09     1025 decompo-  yellow 3.5 13765-19-0

chromate (VI)    x 2H2O                         sition



Calcium-         CaCr2O4 208.07     4.8 2090   - olive- insoluble

chromium (III)-                                                      green



For vapour pressure at 20°C, no data.

    The earth's most important deposits of chromium are in either 

the elemental or the trivalent oxidation state. Hexavalent 

compounds of chromium in the biosphere are predominantly man-made, 

and experience with hexavalent chromium is relatively short.  

Chromates and dichromates are produced from chromite ore by 

roasting in the presence of soda ash. From these, chromium (VI) 

oxide, (CrO3), is precipitated out by the addition of sulfuric 

acid.  Sodium and potassium dichromates are widely used 

industrially as sources of other chromium compounds, particularly 

of chromium (VI) oxide, and these processes are a major source of 

hexavalent chromium pollution (US EPA, 1978). 


2.2.  Analytical Methods


    Methods for the determination of chromium in biological and 

environmental samples are developing rapidly, as shown by the fact 

that chromium concentrations in the blood and urine of unexposed 

subjects, reported as normal, have been revised downwards by 2 

orders of magnitude, in only 15 years (Versieck et al., 1978).  

This development is not only due to the increasing powers of 

detection and specificity of more recent methods, but also to the 

better methods of contamination control that have become available.  

For these reasons, all data concerning chromium levels in blood and 

urine (particularly the early results), should be interpreted with 

caution following scrutiny of all experimental details.  On the 

other hand, analytical results concerning the much higher chromium 

levels in foodstuffs and human tissue have not changed as much and 

can be accepted with more confidence. However, all interpretations 

of chromium data should take into account the need for caution 

expressed in section 2.2.2. 


2.2.1.  Sampling


    As chromium is present in biological materials in very low 

concentrations, care must be taken to avoid contamination. The 

collection of dust from air samples may introduce contamination 

from the chromium in the filters; blood or tissue samples may 

become highly contaminated by the chromium in needles, knives, 

blenders, and other instruments (Behne & Brätter, 1979).  Water 

samples may extract chromium from containers.  Finally, reagents 

used in sample dissolution, separation, chelation, acid digestion, 

and other reactions, may contribute significant amounts of 

chromium.  Thus, it is necessary to control for these influences by 

simultaneously performing a blank analysis, i.e., by carrying out 

the whole analysis, including sampling, preparation, and digestion, 

using all reagents, excluding a sample (Davis & Grossman, 1971). 


    Conversely, chromium in low concentrations may be adsorbed on 

the surface of containers during long periods of storage. This 

aspect has not yet been sufficiently investigated (Shendrikar & 

West, 1974).  Procedures for the sampling of different materials 

for chromium determination have been reviewed by Beyermann (1962), 

Brown et al. (1970), Murrman et al. (1971), Versieck & Speecke 

(1972), Skogerboe (1974), Johnson (1974), and US DHEW (1975).  All 

suggest strictest contamination control (clean rooms or laminar 

flow facilities). 


2.2.2.  Analytical methods


    The voluminous literature on analysis for chromium was reviewed 

by US EPA (1978).  A discussion on analytical methods must 

distinguish between two categories: (a) methods for measuring 

large, potentially toxic concentrations of chromium as a 

contaminant, and (b) methods of analysis for chromium as an 

essential nutrient.  The first category requires reliable 

determinations of chromium at the µg/kg level; the second requires 

greater sensitivity, e.g., to determine accurately the chromium 

level in urine at several hundred ng/litre. 


    The sensitivity of instrumental analysis for the determination 

of chromium does not present any problems for concentrations in the 

mg/kg range, and a number of techniques can furnish satisfactory 

precision and accuracy (Table 2).  On the other hand, the 

sensitivity of instrumentation for the determination of chromium in 

the ng or µg/kg range is severely limited, and no one method is 

entirely satisfactory, at present (Seeling et al., 1979).  The 

biologically active concentrations are near the detection limits of 

the most sensitive methods, such as neutron activation analysis or 

flameless atomic absorption spectrometry.  In an inter-laboratory 

comparison, there was poor agreement between the analytical results 

obtained by well-established, experienced analytical laboratories 

in several countries (Parr, 1977). Some of the results are 

presented in the Table 3.  It is of paramount importance for the 

interpretation of all published analytical data on chromium to 

realize the great variation in reported results, even for high 

concentrations.  These results indicate the following conclusions: 

  1. No one analytical method can be expected to produce

    "true" results of absolute chromium concentrations, unless

    the analyses are controlled by the use of a certified

    reference material with a matrix composition similar to

    that of the material to be analysed.


  1. No valid comparisons can be made on the basis of

    analytical results obtained by different laboratories,

    unless the same reference materials have been used by

    both, or samples have been exchanged.


  1. There is a great need for certified Standard

    Reference Materials with many different matrix

    compositions.  Six such standards of biological materials

    have been certified for chromium content (tomato leaves,

    pine needles, citrus leaves, oyster tissue, unexposed

    bovine serum, and brewer's yeast).  In addition, seven

    standard reference materials of environmental samples are

    available (coal, fly ash, water, sediment, urban

    particulate, etc.) and more than 180 industrial samples of

    various steels and metal alloys.  These are available from

    the National Bureau of Standards, Washington DC, USA.  New

    reference specimens of blood and urine have been produced


    for the quality control of heavy metals in industrial

    medicine and toxicology (Müller-Wiegand et al., 1983).

    The assigned values were determined by reference

    laboratories of the "Deutsche Gesellschaft für

    Arbeitsmedizin; the control blood and urine preparations

    are offered by Behringwerke AG, D-3550 Marburg, Federal

    Republic of Germany.


  1. In inter-laboratory quality assurance studies, it is

    preferable to use the methodology developed in the

    WHO/UNEP project on biological monitoring for lead and

    cadmium (Vahter, 1982).


    In 1983, the German DIN-Committee AAS adopted a method for the

determination of the chromium content of water and sewage (by means

of the flame AAS) (Kempf & Sonneborn, 1976); inductively coupled

plasma emission spectrometry is recommended with regard to serial

analyses (Kempf & Sonneborn, 1981).


    Two special problems in the analysis for chromium may add to, 

or subtract from, the true concentrations, i.e., contamination and 

possible loss through volatilization or formation of refractory 

compounds during sample preparation. Contamination is a serious 

problem when low concentrations in blood or urine are measured.  

Dust in laboratories may contain a chromium level of 700 mg/kg 

(Mertz, 1969), approximately 6 orders of magnitude higher than the 

concentration in urine of 0.2 - 0.7 µg/litre (Guthrie et al., 

1979).  In other words, contamination of a one-ml urine sample by 

only 1 µg of dust will increase the apparent chromium concentration 

two-fold. Special precautions, such as those proposed by Tölg 

(1974), must be taken to control this problem.  The second problem, 

that of potential loss during sample preparation, has been 

discussed by Wolf & Greene (1976).  There is evidence from several 

studies that certain methods of sample preparation, such as heating 

or acid digestion in open systems, may lead to the loss of 

detectable amounts of chromium (Kotz et al., 1972).  A typical 

example, in which identical samples were determined by the 

identical method, by the same analyst, in the same laboratory is 

presented in Table 4. 

Table 2.  Instrumental methods for the determination of chromiuma


Analytical          Relevant Detection    Interfering substance Selectivity

method              applications limit


Atomic              fresh and saline 2 µg/litreb  interfering substances all of the extracted 

absorption          water, industrial               present in the original chromium is measured, 

spectroscopy        waste fluids,               sample are usually not but only hexavalent 

(flame)             dust, and sediments               extracted into the chromium is extracted 

                    biological solids                 organic solvent from the original sample,

                    and liquids, alloys                                        unless oxidative 

                                                                               pretreatment is used



Atomic              biological solids 0.005 µg/    no interfering sub- total chromium is 

absorption          and fluids; tissue, litreb       substances reported determined

(electrothermal)    blood, urine;               for samples of urinen,

                    industrial waste                  and bloodo; less than 

                    waters                            10% interference ob-  

                                                      served for Na+, K+,   

                                                      Ca2+, Mg3+, Cl-,      

                                                      F-, SO4-3, and PO4-3  

                                                      in certain industrial 

                                                      waste watersp         


Emission            a wide variety of 4 µg/litrel  no interfering total chromium is 

spectroscopy        biological and               substances reported determined

(inductively-       environmental

coupled plasma      samples      




Emission            a wide variety of 0.5 ngc                               total chromium is 

spectroscopy        environmental                                       determined

(arc)               samples



Table 2.  (contd.)


Analytical          Relevant Detection    Interfering substance Selectivity

method              applications limit



Spectrophotometry   natural water and 3 µg/litred  iron, vanadium, and after chelation, only 

                    industrial waste                  mercury may interfere the hexavalent chromium 

                    solutions having                                           in solution is determined

                    5 - 400 mg hexa-

                    valent chromium/

                    litre can be 

                    analysed; higher 


                    must be reduced 

                    by dilution 


X-ray fluorescence  atmospheric 2 - 10 µg/g  the particle size of total chromium is 

                    particulates,        (liver)e; the sample and the       determined

                    geological           1.5 µg/g matrix may influence

                    materials            (coal)f the observed measure-



Neutron activation  air pollution depends on   interference may arise total chromium is 

analysis            particulates, activation   from gamma ray activity measured

                    fresh and saline     procedure; from other elements,

                    waters, biological   typical especially Na-24, Cl-38,

                    liquids and solids,  limit: K-42, and Mn-56; P-32

                    sediments, metals,   10 ngm may also cause inter-

                    foods                             ference


Gas chromatography  blood, serum, 0.03 pgg     excess chelating agent only chromium that is 

(electron capture   natural water               or other electron- chelated and extracted

detection)          samples               capturing constituents is measured; other 

                                                      in the sample may lead   electro-negative substances  

                                                      to erroneous results     may elute from the column

                                                                               and be detected at the

                                                                               same time as the chromium    



Stable isotope      all biological               not expected high precision and accuracy

dilution mass       materialsk,q                                       (1%) complete sample  

spectrometry                                                                   digestion and exchange of

                                                                               endogenous chromium with

                                                                               added stable isotope



Table 2.  (contd.)


Analytical          Relevant Detection    Interfering substance Selectivity

method              applications limit


Gas chromatography  blood, serum, ~1 ngh       no interference only chromium that is  

(atomic             biological material               reported chelated and extracted is

spectroscopic                                                                  detected; atomic 

detection)                                                                     spectroscopic methods   

                                                                               of detection are 

                                                                               inherently more selective

                                                                               for chromium in complex



Gas chromatography  blood, plasma, 0.5 pgi      no interference only chromium that is 

(mass               serum               reported chelated and extracted 

spectrometric                                                                  can be detected



Chemiluminescence   fresh, natural 30 ng/       Co(II), Fe(II), and only trivalent chromium 

                    waters; dissolved    litrek Fe(III) interfere but    ion is measured

                    biological material               may be compensated for

                                                      by running a blankc


a   Modified from: US EPA (1978).

b   From: Welz (1983).

c   From: Seeley & Skogerboe (1974).

d   From: American Public Health Association, American Water Works Association,

    and Water Pollution Control Federation  (1971).

e   From: Kemp et al. (1974).

f   From: Kuhn (1973).

g   From: Savory et al. (1969).

h   From: Wolf (1976).

i   From: Wolf et al. (1972).

k   From: Seitz et al. (1972).

l   From: Welz (1980).

m   From: Keller (1980).

n   From: Schaller et al. (1973).

o   From: Environmental Instrumentation Group (1973).

p   From: Morrow & McElhaney (1974).

q   From: Veillon et al. (1979).

Table 3.  Results for 3 IAEA intercomparison studiesa


Laboratory  Method Number of       Laboratory SD (%)

code        codeb determinations  mean


  1. Simulated air filter

   (true chromium concentration: 1.85 µg/filter)


a           7 2               1.3 3

b           3 1               1.6 7

c           2 4               1.78 5

d           2 10              1.85 6

e           2 6               1.86 52

f           2 2               2.00 30

g           2 3               2.07 10

h           2 6               2.07 9

i           2 6               2.07 6

j           7 10              2.16 10

k           5 6               2.83 40

l           7 2               3.00 -c

m           3 5               3.17 4

n           7 1               4.20 8

o           2 5               6.14 6

p           2 1               7.50 22


  1. Water

   (true chromium concentration: 11.1 µg/kg)


a           3 4               1.85 18

b           3 5               3.80 12

c           7 6               4.16 15

d           7 1               4.50 11

e           7 6               4.77 6

f           7 2               5.25 -

g           2 5               5.51 3

h           2 5               5.84 4

i           7 1               6.00 -

j           2 3               6.08 4

k           7 2               6.50 -

l           7 2               6.85 17

m           2 2               7.00 -

n           7 2               7.30 -

o           7 3               8.67 3

p           7 2               8.90 20

q           3 1               9.00 20

r           7 5               9.60 12

s           7 6               9.92 10

t           2 5               10.8 11

u           2 4               11.3 11

v           7 3               11.5 45

w           5 2               18.0 30

x           7 1               73.0 14



Table 3.  (contd.)


Laboratory  Method Number of       Laboratory SD (%)

code        codeb determinations  mean


  1. Bovine liver (SRM 1577)

   (certified chromium concentration: 88 ± 12 µg/kg)


a           2 -c              5 -c

b           1 -c              51 13

c           1 -c              140 -c

d           2 -c              150 13

e           1 -c              150 33

f           1 -c              160 24

g           1 -c              240 53

h           2 -c              490 39

i           1 -c              540 64

j           2 -c              1300 -c

k           2 -c              1600 25


a   From: Parr (1977).

b   Method code:

  1. Destructive activation analysis.
  2. Nondestructive activation analysis.
  3. Emission spectroscopy.
  4. Spark source mass spectrometry.
  5. Atomic absorption, unspecified.

c   Information not given.

    At present, there is no explanation of the reason why "losses" 

of almost 90% were associated with the direct graphite furnace 

ashing, compared with oxygen plasma ashing in the case of molasses, 

but not of refined sugar.  Canfield & Doisy (1976) and Tuman et al. 

(1978) suggested that the loss of chromium in biological samples, 

such as urine, yeast extracts, or synthetic glucose tolerance 

factor (GTF) preparations represented the biologically active GTF 

fraction of the chromium.  They correlated this "volatile" fraction 

in yeast extracts with the antidiabetic activity of the extract in 

genetically diabetic mice, and the amount of "volatile" chromium in 

the urine of human subjects with the efficiency of the glucose 

metabolism of these subjects.  This hypothesis of "volatile" 

chromium has been confirmed by some investigators (Behne et al., 

1976; Koirtyohann & Hopkins, 1976; Shapcott et al., 1977; 

McClendon, 1978), and contradicted by others (Jones et al., 1975; 

Rook & Wolf, 1977).  While the question of the "volatility" of 

chromium, under various conditions, remains unanswered, it is 

obvious that chromium determination presents many problems, the 

most pressing of which is the selection and control of sample 

digestion (Wolf & Greene, 1976). 


Table 4.  Apparent chromium content depending on the method of 



Type of sugar      Number Chromium content + SEM (µg/kg)   

                   of       Oxygen   Muffle Graphite 

                   samples  plasma   furnace furnace ashing

                            ashing     ashing (1000 °C)

                            (150 °C)   (450 °C) (direct



molasses           3 266 ± 50 129 ± 54  29 ± 5

sugar (unrefined)  8 162 ± 36 88 ± 20   37 ± 13

sugar (brown)      5 64 ± 5 53 ± 8    31 ± 2

sugar (refined)    7 20 ± 3 25 ± 3    < 10


a   From: Wolf et al. (1974).


    Finally, it is important in any study of the environmental 

effects of chromium, to distinguish analytically between the 

trivalent and hexavalent forms.  This can be accomplished by 

dithiocarbamate chelation and solvent extraction (for example, with 

methyl isobutylketone) prior to oxidation.  Only the hexavalent 

chromium remains after this process, and thus it is possible to 

differentiate between the oxidation states (Feldman et al., 1967; 

Cresser & Hargitt, 1976; Bergmann & Hardt, 1979; Joschi & Neeb, 

1980).  When determining chromium in biomaterial, the samples are 

usually ashed with strong acids to destroy the organic components.  

The relationship between the acids used and the behaviour of 

chromium were investigated by Hara (1982) who showed that the 

oxidation state of chromium was apt to change (hexavalent to 

trivalent), because of the reducing action of each acid and the 

conditions under which they were used. 




3.1.  Natural Occurrence


    Chromium is ubiquitous in nature; it can be detected in all 

matter in concentrations ranging from less than 0.1 µg/m3 in air to 

4 g/kg in soils.  Naturally occurring chromium is almost always 

present in the trivalent state: hexavalent chromium in the 

environment is almost totally derived from human activities. 


    Merian (1984) has compiled the global sources of chromium in 

the environment.  Total input (100%) consists of inputs by: 

volcanic emissions (less than 1%); the biological cycle (30%) 

including extraction from soil by plants (15%) and weathering of 

rocks and soils (15%); and man-made emissions (70%) including those 

from general ore and metal production (3%), from metal use (60%), 

and from coal burning and other combustion processes (7%). 


3.1.1.  Rocks


    Almost all the sources of chromium in the earth's crust are in 

the trivalent state, the most important mineral deposit being in 

the form of chromite (FeOCr2O3) which, however, is rarely pure.  

Living matter does not produce the energy necessary to oxidize 

trivalent to hexavalent chromium in the organism, therefore, it can 

be stated that nearly all hexavalent chromium in the environment is 

produced by human activities.  The industrial use of chromium and 

the oxidation to the hexavalent state on an industrial scale did 

not begin until 1816.  Thus, man's experience with this form is 

very short. 


    The concentration of chromium in rocks varies from an average 

of 5 mg/kg (range of 2 - 60 mg/kg) in granitic rocks, to an average 

1800 mg/kg (range, 1100 - 3400 mg/kg) in ultrabasic and serpentine 

rocks (US NAS, 1974b). 


    Chromium deposits in the hexavalent oxidation state (crocoite 

PbCrO4), were described by Lomonossow, in the year 1763 (Hintze, 

1930), who found it in the Ural Mountains. Being a rare mineral, 

chromium is found in the oxidized zones of lead deposits in regions 

in which lead veins have traversed rocks containing chromite.  It 

may be associated with pyromorphite, cerussite, and wulfenite.  

Notable localities are: Dundas, Tasmania; Beresovsk near 

Sverdlovsk, Ural Mountains (Aleksandrov & Kainov, 1975), and 

Rezbanya, Rumania.  It is found in small quantities in the Vulture 

district, Arizona, USA (Dana, 1971) and in the German Democratic 

Republic in Callenberg, Saxony (Rohde et al., 1978). 


    Chromium concentrations in igneous rocks are positively 

correlated with concentrations of silica, magnesium, and nickel.  

Of agricultural importance, is the high chromium concentration in 

sedimentary rocks, where the element is present in phosphorites.  

This material is used as a phosphate fertilizer in agriculture and 

is a significant source of chromium for agricultural soils. 


    Chromium-containing rocks and ores are found in all regions of 

the world, but the major sources of the world's chromium supplies 

are the ultra basic rocks of South Africa, Turkey, the USSR and 

Zimbabwe (US NAS, 1974b).  While underlying undisturbed rocks 

contribute little chromium to the vegetation directly, the chromium 

content is strongly correlated with that of the overlying soils. 


    Chromium can also be found in coal (5 - 10 mg/kg) (Merian, 



3.1.2.  Soils


    The weathering of rocks produces chromium complexes that are 

almost exclusively in the trivalent state.  In most soils, chromium 

occurs in low concentrations; an average of 863 soil samples from 

the USA contained 53 mg/kg (Shacklette et al., 1970).  The highest 

concentrations, as high as 3.5 g/kg (Swaine & Mitchell, 1960), are 

always found in serpentine soils.  In a small area in Maryland, 

USA, with soil infertility, the chromium concentration (as Cr2O3) 

was as high as 27.4 g/kg (Robinson & Edington, 1935).  Conversely, 

low chromium concentrations (10 - 40 mg/kg) have been detected in 

soils derived from granite or sandstone (Swaine & Mitchell, 1960).  

Only a fraction of the chromium in soil is available to the plant; 

thus, it is important to determine "available" soil-chromium.  A 

rough approximation of this available chromium fraction can be made 

by extracting soil with acids or chelating agents and by measuring 

the chromium in the extract.  Though the amount of extractable 

chromium is not identical with that truly available to the plant, 

it is a much better measure of availability than the total 

chromium.  In the study of Swaine & Mitchell (1960), the amount of 

chromium extracted from the soil with acetic acid varied much less 

than the total soil content, and was not correlated with the latter 

(Table 5). 


    The comparisons in this Table indicate that the amount of 

chromium available to the plant is relatively independent of the 

total concentration.  The complex principles determining the 

availability of chromium for plants are poorly understood. 


Table 5.  Total versus extractable chromium in different 

Scottish soilsa


Soil             Total chromium   Extractable chromium

derived from:    (mg/kg)   (mg/kg)


Granite          20, 40, 20   0.15, 0.1, 0.11


Serpentine,      3500, 2000, 3000   0.31, 0.24, 0.63



a   From: Swaine & Mitchell (1960).


3.1.3.  Water


    It is now generally agreed that, except in areas with 

substantial chromium deposits, high chromium levels in water arise 

from industrial sources (US NAS, 1974b). 


    With the exception of areas bearing chromium deposits or in 

highly industrialized areas, most surface waters contain very low 

levels of chromium.  The chromium content in surface water in the 

Tia-ding county, Shanghai, ranged from 0 to 80 µg/litre (256 

samples).  According to the Yang-Pu water works, which is the 

biggest water works in Shanghai, the chromium levels in well water 

are below 50 µg/litre.  Between 1980 and 1982, chromium was not 

detectable in the Yellow River.  There is no information concerning 

the analytical methods used (Chen Bingheng, personal communication 

to the Task Group, 1986).  Kopp & Kroner (1968) detected chromium 

in only 25% of surface water samples from sources in the USA, with 

a range of 1 - 112 µg/litre, and a mean concentration of 9.7 

µg/litre.  The remaining 75% contained less than 1 µg/litre, the 

detection limit.  Another survey of 15 rivers in the USA revealed 

levels ranging from 0.7 to 84 µg/litre, the majority of samples 

containing between 1 and 10 µg/litre (Durum & Haffty, 1963).  On 

the other hand, chromium contents in natural water of up to 215 

µg/litre were reported by Novakova et al. (1974).  Although modern 

methods of water treatment remove much of the naturally present 

chromium, it should be noted that chlorinated drinking-water 

usually contains traces of hexavalent chromium.  The mean level in 

the drinking-water supplies in 100 cities in the USA was only 0.43 

µg/litre, with a range from barely detectable to 35 µg/litre 

(Durfor & Becker, 1964). 


    Sea water contains less than 1 µg chromium/litre (US NAS, 

1974b), but the exact chemical forms in which chromium is present 

in the ocean, and surface water are not known. Theoretically, 

chromium can persist in the hexavalent state in water with a low 

organic matter content.  In the trivalent form, chromium will form 

insoluble compounds at the natural pH of water, unless protected by 

complex formation.  The exact distribution between the trivalent 

and hexavalent state is unknown. 


3.1.4.  Air


    Chromium occurs in the air of non-industrialized areas in 

concentrations of less than 0.1 µg/m3.  The natural sources of air-

chromium are forest fires and, perhaps, volcanic eruptions (section 

3.5).  Man-made sources include all types of combustion and 

emissions by the chromium industry (section 4.1.1).  The chemical 

forms of chromium in the air are not known, but it should be 

assumed that part of the air-chromium exists in the hexavalent 

form, especially that derived from high-temperature combustion.  

Chromium trioxide (CrO3) may be the most important compound in the 

air (Sullivan, 1969). 


3.1.5.  Plants and wildlife


    It is not known whether chromium is an essential nutrient for 

plants, but all plants contain the element in concentrations 

detectable by modern methods. 


    Chromium concentrations in food plants growing on normal soils 

range from not detectable to 0.19 mg/kg wet weight (Schoeder et 

al., 1962).  In addition, chromium of vegetable origin has a 

relatively low biological activity (Toepfer et al., 1973). 


    Much higher concentrations have been reported in plants growing 

on chromium deposits.  For example, ash analysis showed a chromium 

level of 0.34% in New Zealand lichen and 0.3% in Yugoslav  Allysium 

 markgrafi (US NAS, 1974b).  Growing on a serpentine soil (chromium 

concentration 62 000 mg/kg in old mine tailings), the plant 

chromium concentrations (on the basis of ash analysis) ranged from 

700 mg/kg in  Phormium colensoi and  Liliacae to 5400 mg/kg in 

 Gentiana corymbifera (Lyon et al., 1970).  Not all plants tolerate 

high concentrations of available soil-chromium; chlorosis of citrus 

trees has been observed in high-chromium areas and in laboratory 

experiments.  Plants grown in the vicinity of chromium-emitting 

industries or those fertilized by sewage sludge are exposed to 

substantial amounts of chromium.  The chromium contents of plants 

growing were determined by Taylor et al. (1975) near cooling 

towers, where chromates were present as corrosion inhibitors.  It 

was shown that chromium levels in grasses, trees, and litter, 

decreased with increasing distance from the towers.  No information 

was given as to whether the variations in chromium concentrations 

were the result of surface contamination or of true absorption by 

the roots of the plant. 


    The atmospheric deposition of metals and their retention in 

ecosystems were studied by Mayer (1983).  He measured mean annual 

deposition rates in a beech and spruce forest ecosystem in the 

Solling (Federal Republic of Germany) in 1974-78 and found that 

chromium deposition in the forest canopy was in the range of 13.5 - 

15.1 mg/m2 per year; the deposition on the soil below the forest 

canopy ranged from 1.6 to 2.3 mg/m2 per year.  Thus, up to 80% of 

the metals from the atmosphere were retained in the canopy, and 30 

- 50% of chromium remained in the noncycling parts of forest 

biomass (bark and wood). 


    Sewage sludge can contain chromium levels as high as 9000 

mg/kg.  Application of sewage sludge to soils, which increased the 

chromium levels from 36.1 to 61 mg/kg on a dry weight basis, 

increased the contents of chromium in plants growing in the soil 

from, e.g., 2.6 to 4.1 mg/kg in fodder rape (Andersson & Nilsson, 

1972).  However, most of the increased uptake in plants is retained 

in the roots, and only a small fraction appears in the edible part 

(Cary et al., 1977).  Other elements within the sludge, e.g., 

cadmium or nickel, pose a greater problem for human health (Chaney, 



    Of particular importance is the chromium concentration in the 

forage of meat animals.  Kirchgessner et al. (1960) found strong 

seasonal variations in the chromium levels in 3 different kinds of 

grasses; the highest level found was 590 µg/kg dry weight in hay. 


    Higher levels of chromium in vegetation not used for human 

consumption may account for the generally higher chromium contents 

in the organs of wild animals, compared with man (Schroeder, 1966). 


    Schroeder (1970) determined the chromium concentrations in 

different organs and muscles of wild animals and found that they 

ranged from 0.04 to 0.48 mg/kg on a wet weight basis. Chromium 

concentrations in the hair of several wild-animal species, 

collected by Huckabee et al. (1972), ranged from 640 mg/kg in a 

pronghorn antelope living in Lemhi Range, Idaho, USA, to about 0.6 

mg/kg in a coyote, sampled in Jackson Hole, Wyoming, USA. 


3.1.6.  Environmental contamination from natural sources


    No data have been found that indicate any significant 

contamination of the environment from natural sources, though major 

catastrophic events, such as large forest fires or volcanic 

eruptions, could conceivably contribute to the concentration of 

chromium in air.  Water supplies originating in areas with chromium 

deposits may contain elevated chromium concentrations (section 

4.1.2).  However, none of these natural sources contributes enough 

chromium to pose a hazard for human or animal health. 


3.2.  Production, Consumption, and Uses


    The world's mining production of chromium ore was approximately 

9.73 million tonnes (gross weight) in 1980; it fell to 9 million 

during 1981 (Thomson, 1982), but rose again to 11 million tonnes in 

  1. Exact data on the yield of elemental chromium are not 

available, but may range around half of the gross weight of the 

mined ore. 


    The major uses and amounts of chromium used in the USA in 1968 

in thousands of tonnes were: transportation, 77; construction 

products, 105; machinery and equipment, 72; home appliances and 

equipment, 25; refractory products, 68; plating of metals, 20; 

pigment and paints, 15; leather goods, 10; and other uses, 66; 

giving a total of 458 thousand tonnes. 


    The principal uses of chromium are in the metallurgical 

processing of ferrochromium and other metallurgical products, 

chiefly stainless steel, and, to a much lesser extent, in the 

refractory processing of chrome bricks and chemical processing to 

make chromic acid and chromates. 


    Chromates are used for the oxidation of various organic 

materials, in the purification of chemicals, in inorganic 

oxidation, and in the production of pigments.  A large percentage 

of chromic acid is used for plating.  Dichromate is converted to 

chromic sulfate for tanning.  Fungicides and wood preservatives 

consume an estimated 1.3 million kg of chromium annually.  

Chromates are used as rust and corrosion inhibitors, for example, 

in diesel engines.  Because chromite has a high melting point and 

is chemically inert, it is used in the manufacture of bricks for 

lining metallurgical furnaces. 


    In 1981, the demand for chromium was at its lowest level since 

  1. However, on the basis of 1978 figures, the demand for 

chromium is expected to increase at an annual rate of about 3.2%, 

up to 1990.  While the level of stainless steel production will 

continue to be the principal influence affecting markets for 

chromite and ferrochrome, other factors could have a significant 

impact on future trends, e.g., purchases for government stockpiles 

(in 1981, the USA had a stockpile of 1.48 million tonnes, and 

France and Japan announced the build up of stockpiles) or the 

development of new alloys and steels (Thomson, 1982). 


3.3.  Waste Disposal


    Substantial amounts of chromium enter sewage-treatment plants 

in major cities.  Klein et al. (1974) estimated a total daily 

chromium burden for New York city treatment plants of 676 kg, of 

which 43% came from electroplating, 9% from other industries, 9% 

from runoff, 11% from unknown sources, and 28% from residential 

homes.  This waste from one city alone (amounting to 2.4 x 105 

kg/year), if untreated, would add a significant burden to the 

ocean, in comparison with the estimated global natural chromium 

mobilization by weathering of 3.6 x 107 kg/year (Bertine & 

Goldberg, 1971).  The high chromium discharge from homes is 

difficult to explain; it has been suggested that this could arise 

from the corrosion of stainless steel or the use of waste disposal 

units in domestic sinks.  The contribution from excreta, estimated 

at 100 µg chromium/day per person, should not exceed 1 kg/day for 

the 10 million people in the New York area. 


    The concentration of chromium in the waste-water received at 

the New York treatment plants varied between 40 and 500 µg/litre; 

this range is probably representative of the chromium discharge in 

major cities.  The removal of chromium from the waste-water was 

studied by Brown et al. (1973). Primary sewage treatment removed 

only 27%, secondary treatment using a trickling-filter method 

removed 38%; the most effective secondary treatment method 

(activated sludge) removed 78%.  In another study of a treatment 


plant (Chen et al., 1974), the primary effluent contained 300 

µg/litre and the secondary effluent, after the activated sewage 

sludge and sedimentation process, 60 µg/litre (80% removal).  The 

final discharge from the plant, a mixture of primary and secondary 

effluent and digested sludge had quite a high chromium content of 

200 µg/litre.  This level is substantially higher than the natural 

chromium content of surface water and represents a significant 

source of contamination. 


    Waste-waters from chromium industries contain very high levels 

of chromium, ranging from 40 mg/litre (leather industry) to 50 000 

mg/litre (chromium plating) (Cheremisinoff & Habib, 1972).  These 

levels must be reduced by precipitation before the waste-water can 

be discharged.  The steps include reduction of hexavalent to 

trivalent chromium at an acidic pH, followed by precipitation of 

the hydroxides at pH 9.5 (Ottinger et al., 1973).  The precipitates 

containing chromium and other metals are then collected in settling 

ponds and disposed of by landfill, incineration, or dumping in the 

ocean (US EPA, 1980).  If the last procedure is used, the waste-

water treatment itself will contribute to the contamination of the 



    Landfill and sewage sludge operations are, in turn, potential 

sources of contamination of soil and groundwater by chromium.  

However, at alkaline pH values, chromium hydroxides are insoluble 

and leaching by any but very acidic water should be minimal.  

Pohland (1975) did not detect any measurable concentrations of 

chromium in the leachate from a simulated landfill. 


    Similary, the chromium in sewage sludge is very poorly soluble.  

Berrow & Webber (1972) found a mean concentration of only 22 

mg/litre (range, < 0.9 - 170 mg/litre) in samples of 42 sludges 

extracted with 2.5% acetic acid.  This represented 0.7 - 8.5% of 

the chromium concentration in the original sludge.  As acetic acid 

is a good complexing and extracting agent for chromium, the 

reported levels of extractable chromium are probably much greater 

than those resulting from extraction with water at near neutral pH.  

However, sludge application to land does increase the chromium 

content of the soil (LeRiche, 1968).  The application of 66 

tonnes/hectare each year, for 19 years, resulted in an increase in 

the acetic acid-soluble chromium in the soil from 0.9 to 2.6 mg/kg, 

7 years after sludge application was discontinued.  This 

extractable chromium is presumably available to the plant. The 

final link in the cycle of the soil-chromium derived from sewage 

sludge is not well known.  Undoubtedly, some will be removed by the 

growth of vegetation (section 3.1.5).  The rate of migration into 

ground water depends on the properties of the soil and climatic 

conditions.  Thus, it is not surprising that, in one study 

(LeRiche, 1968), a very slow rate of disappearance was reported 

(reduction of extractable chromium from 2.8 to 2.6 mg/kg in 8 

years), whereas in another, there was a very rapid rate of 

disappearance (reduction of total chromium from 118 to 30 mg/kg, in 

3 years) (Page, 1974). 


3.4.  Miscellaneous Sources of Pollution


    As discussed earlier, waste-waters from residential areas in 

New York carried approximately 200 kg of chromium daily to the 

treatment plants.  Of this amount, only 1 kg can be accounted for 

by the human excreta of 10 million persons.  If a water use of 200 

litres per person and a (high) chromium content of 10 µg/litre is 

assumed, this concentration would account only for an additional 20 

  1. The origin of the rest is unknown (section 3.3).  It should be 

pointed out that analytical accuracy is difficult to achieve in 

chromium analysis (section 2.2.2) and will affect the results of 

all "balance" calculations. 


    It is evident that the chief source of air pollution with 

chromium is ferrochromium refining.  Appreciable, but far smaller 

emissions, come from refractory operations and inadvertent sources.  

The lowest emissions come from the chemical processes in the 

production of dichromate and other chrome chemicals.  Combustion of 

coal and oil, and cement production, large-scale, spray-painting 

operations (e.g., ships and planes) and glass plants constitute 

other major sources of chromium emissions. 


3.5.  Environmental Transport and Distribution


    Industrial effluents containing chromium, some of which is in 

the hexavalent form, are emitted into streams and the air. Whether 

the chromium remains hexavalent until it reaches the ocean depends 

on the amount of organic matter present in the water.  If it is 

present in large quantities, the hexavalent chromium may be reduced 

by, and the trivalent chromium adsorbed on, the particulate matter.  

If it is not adsorbed, the trivalent chromium will form large, 

polynucleate complexes that are no longer soluble.  These may 

remain in colloidal suspension and be transported to the ocean as 

such, or they may precipitate and become part of the stream 

sediment. Similar processes occur in the oceans: hexavalent 

chromium is reduced and settles on the ocean bed.  It is replaced 

by an estimated 6.7 x 106 kg of chromium from rivers (Bowen, 1966). 

In a study of the oxidation state of chromium in ocean water, Fukai 

(1967) detected an increased proportion of the trivalent form with 

increasing depth. 


    Chromium is emitted into the air, not only by the chromium 

industries, but also by every combustion process, including forest 

fires.  The oxidation state of chromium emissions is not well 

defined quantitatively, but it can be assumed that the heat of 

combustion may oxidize an unknown proportion of the element to the 

hexavalent state.  While suspended in the air, this state is 

probably stable, until it settles down and comes into contact with 

organic matter, which will eventually reduce it to the trivalent 

form.  Living plants and animals absorb the hexavalent form in 

preference to the trivalent, but once absorbed, it is reduced to 

the stable, trivalent state. 


    The transport of chromium in the environment is summarized in 

Fig. 1.  It should be noted that there is a complete cycle from 

rocks or soil to plants, animals, and man, and back to soil.  Only 

part of the chromium is diverted to a second pathway leading to the 

repository, the ocean floor.  This part consists of chromium from 

rocks and soil carried by water (concentrations, a few µg/litre) 

and animal and human excreta, a small part of which may find their 

way into water (e.g., runoff from sewage sludge).  Another cycle 

consists of airborne chromium from natural sources, such as fires, 

and from the chromate industry.  This cycle also contains some 

hexavalent chromium, with byproducts going into the water and air.  

Part of the air-chromium completes the cycle by settling  on the 

land, but a very significant portion goes into the repository, the 

ocean, where it ends up as sediment on the ocean floor. 






4.1.  Environmental Levels


4.1.1.  Air


    Chromium concentrations in air vary with location. Background 

levels determined at the South Pole ranged from 2.5 to 10 pg/m3 and 

are believed to be due to the weathering of crustal material (US 

NAS, 1974a).  Data collected by the US National Air Sampling 

Network in 1964 gave the national average concentration for 

chromium in the ambient air as 0.015 µg/m3, varying from non-

measurable levels to a maximum of 0.35 µg/m3.  Chromium 

concentrations in most non-urban areas and even in many urban areas 

were below detection levels.  Yearly average concentrations for 

cities in the USA varied from 0.009 to 0.102 µg/m3.  Concentrations 

ranging from 0.017 to 0.087 µg/m3 have been reported for Osaka, 

Japan (US EPA, 1978).  The chromium content of the air in the 

vicinity of industrial plants may be higher.  In 1973, the reported 

chromium concentrations ranged from 1 to 100 mg/m3 for coal-fired 

power plants, from 100 to 1000 mg/m3 for cement plants, from 10 to 

100 mg/m3 for iron and steel industries, and from 100 to 1000 mg/m3 

for municipal incinerators (US EPA, 1978).  Ferrochromium plants 

have the highest emission rates (Radian Corporation, 1983).  

However, modern chromium chemical plants contribute very little to 

pollution today, because of the installation of collecting 

equipment that returns the material for reuse.  Drift from cooling-

towers contributes to atmospheric pollution, when chromium is used 

as a corrosion inhibitor (section 3.1.5).  Little information 

exists on the particle size distribution of chromium in the air.  

The mass median diameter in a study in the United Kingdom was 

1.5 µm (Cawse, 1974). 


    The chemical form of chromium in air depends on the source.  

Chromium from metallurgical production is usually in the trivalent 

or zero state.  During chromate production, chromate dusts can be 

emitted.  Aerosols containing chromic acid can be produced during 

the chrome-plating process; chromate is also the form found in air 

contaminated by cooling-tower drift. 


4.1.2.  Water


    Except for regions with substantial chromium deposits, the 

natural content of chromium in surface waters and drinking-water is 

very low, most of the samples containing between 1 and 10 µg/litre 

(US NAS, 1974a).  Substantially higher concentrations are almost 

always the result of human activities, reflecting pollution from 

industrial activities or sewage waste (Perlmutter & Lieber, 1970).  

Thus, the chromium concentration in untreated surface water 

supplies reflects the extent of the industrial activity in an area 

(Table 6). 

Table 6.  Chromium in water supplies


Country                Chromium Range     Reference

                       concentration  (µg/litre)




   flat district       -a 7 - 8       Novakova et al. 

   hilly district      - 60 - 215    (1974)



   Great Lakes         1 0.2 - 19    Weiler & Chawla 


   Ottawa River        0.01 -       Durum & Haffty 


                                                  Merrit (1971)



   Yellow River        undetectable -       Chen Bingheng 

   Tia-Ding country    - 0 - 80      (personal 

   surface water                                  communication, 1986)


 Germany, Federal                                                     

 Republic of                                                         

   Rhine River         18       DeGroot & Allersma



   Wisla               - 31 - 112    Pasternak (1973)



   Illinois River      21 5 - 38      Mathis & Cummings 


   Lake Tahoe          < 0.07 -       Bond et al. (1973)

   Mississipi River                   3 - 20 Bond et al. (1973)

   New York area,      1250 -       Lieber et al. (1964)

   contaminated stream


a   No data available.

    Drinking-water from 100 public water supplies in the USA had a 

median chromium content of 0.43 µg/litre, ranging from non-

detectable concentrations to 35 µg/litre.  In the Federal Republic 

of Germany, levels in about 90% of drinking-water samples from 1062 

public water supplies were below 0.5 µg/litre; in 1.4% of the water 

samples, levels exceeded the prescribed limit value of 50 µg/litre 

(Kempf & Sonneborn, 1981). 


    Both trivalent and hexavalent forms of chromium occur in water.  

National and international drinking-water standards reject 

drinking-water containing hexavalent chromium concentrations of 

more than 50 µg/litre.  Such high concentrations occur naturally, 

only in areas with substantial chromium deposits (Novakova et al., 

1974); in all other regions they would be caused by industrial 



4.1.3.  Food


    The available food data (Schroeder et al., 1962; Schlettwein-

Gsell & Mommsen-Straub, 1971; Toepfer et al., 1973; Kumpulainen et 

al., 1979) indicate a range of the chromium concentrations in 

different foodstuffs of 5 -250 mg/kg (Table 7).  Highly refined 

foods, such as sugar and flour of low extraction, contain the 

lowest levels.  Very high concentrations have been reported in 

pepper (Schroeder et al., 1962) and brewer's yeast. 


Table 7.  Ranges of chromium concentrations in some 

food groupsa


Food                        Chromium content

                            (µg/kg of wet weight)  

                            Mean      Range


Flour, refined              < 20


Bran                        50


Meat (beef, pork, chicken)            10 - 60


Fish, fresh                           < 10 - 10


Vegetables                            5 - 30


Nuts                        140


Whole Milk                  10


Cheeses                               10 - 130


Sugar, refined              < 20


Egg yolk                    200


a   From: Koivistoinen (1980).


4.2.  General Population Exposure


4.2.1.  Food and water


    The chromium intake from diet and water varies considerably 

between regions (Table 8).  However, these variations should be 

interpreted with caution because not all the analyses have been 

controlled by the use of standard reference material or proper 

quality assurance procedures, and discrepancies in methods cannot 

be completely discounted. 


Table 8.  Chromium intake from diet and water


Region            Chromium Remarks           Reference





Canada            189 -             Canada, National

                  (136 -                        Health and Welfare

                  282)                          (1980)


Germany, Federal  62 DAa; 4 subjects,  Schelenz (1977)

Republic of       (11 - 1 week



Japan             723 urban adults      Murakami et al.

                  (202 -                        (1965)



                  943         rural adultsb     Murakami et al.

                  (> 180 -                     (1965)



New Zealand       81 ± 32 DAa; 11 women,    Guthrie (1973)

                  (39 - 190)  self-selected 



United Kingdom    (80 - 100)             Facer, J.L.



USA               52 DAa             Levine et al.

                  (5 - 115)                     (1968)


USA               78 ± 42 DA; 28 diets,     Kumpulainen 

                  (25 - 224)  complete       et al.

                              (controlled       (1979)

                              by SRM)



  Tatar           (88 - 126) childrend         Goncharov (1968)


a   DA = Direct analysis of composite diets as consumed.

b   Analysis of composite of cooked servings for one complete day

    collected from 10 families in different localities.

c   Personal communication to Dr M. Mercier, IPCS (United Kingdom 

    Ministry of Agriculture, Fisheries and Food, London).

d   Analysis of diets in kindergartens.


    Most reported chromium intakes range from 50 to 200 µg/day.  

However, a comparison of the chromium levels reported by different 

investigators reveals substantial differences, some of which may be 

due to the influence of the location where the foods were grown.  

Only one study (Kumpulainen et al., 1979) was controlled by the use 

of standard reference materials.  The data should therefore be 

treated as preliminary.  Furthermore, data concerning total 

chromium concentrations do not include information on the species 


of chromium in the food and their biological availability.  In an 

attempt to estimate the biologically available chromium in food, 

Toepfer et al. (1973) measured the effects of extracts from foods 

on the potentiation of insulin action in epididymal fat tissue  in 

 vitro.  No correlation was found between the insulin potentiation 

and the total chromium extracted from the foods by acid hydrolysis, 

but a significant correlation ( P = 0.01) appeared between the 

ethanol-extractable amount of chromium and biological activity.  

The highest concentrations of ethanol-extractable chromium were 

found in brewer's yeast, black pepper, calf liver, cheese, and 



4.2.2.  Other exposures


    Since chromium compounds are increasingly present in products 

used in daily life, chromium eczemas are often observed in the 

general population.  Polak et al. (1973) surveyed the most 

important chromium-containing materials or objects: chromium ore, 

baths, colours, lubricating oils, anti-corrosive agents, wood 

preservation salts, cement, cleaning materials, textiles, and 

leather tanned with chromium.  According to Polak et al. (1973), 

people who work with material containing mere traces of chromium 

salts are more at risk than workers who come into contact with high 

concentrations of chromium salts.  Some less frequently occurring 

cases include sensitization by tattooing (especially green and 

light-blue)( Tazelaar, 1970), artificial dentures made of chromium-

containing steel, metal pins used for internal fixation of broken 

bones, and bullets retained in the body (Langard & Hensten-

Pettersen, 1981). 


4.3.  Occupational Exposure


4.3.1.  Inhalation exposure


    In chromium ore mines, the concentration of dust in the air in 

different work-places ranged from 1.3 to 16.9 mg/m3. In the 

crushing and sorting factory, it varied from 6.1 to 148 mg/m3.  The 

chromium content in settled dust (calculated as Cr2O3) varied from 

3.6 to 48%.  During the period 1955-69, levels of trivalent 

chromium in the dust in different work-places in ferro-alloy 

factories ranged from 16 to 42%, while the concentrations of dust 

in the air varied from 14 to 38 mg/m3 (Pokrovskaja & Shabynina, 



    In the past, the production of refined ferrochromium led to 

high concentrations of dust in the air of the work-place (10 - 30 

mg/m3) (Velichkovsky & Pokrovskaja, 1973).  The concentrations of 

hexavalent chromium after implementation of a number of sanitation 

and hygienic measures were 0.03 - 0.06 mg/m3 (Velichkovsky & 

Pokrovskaja, 1973). 


    In the manufacture of chromates, the oxidation state, 

solubility, and composition of air-borne material varied in 

different areas of the plant.  Exposure in the ore-crushing area 

was to trivalent, insoluble particulates; in the leaching area, 


exposure was to tri- and hexavalent, soluble and insoluble 

particulates and droplets; at the dry end of the process, the 

workers were exposed to the very soluble hexavalent chromates in 

particulate form, and to the insoluble residue after leaching 

(Velichkovsky & Pokrovskaja, 1973).  In plants using calcium in the 

roasting process, the residue that is recycled contains, among 

other products, calcium chromate, currently believed, on the basis 

of animal studies, to be at least partly responsible for the 

carcinogenicity of chromium. 


    Chromium plating of metal surfaces was accompanied by the 

release of hexavalent chromium into the air in work premises, in 

concentrations ranging from 0.04 to 0.4 mg/m3 (Yunisova & 

Pavlovskaja, 1975).  In one electroplating factory, the 

concentration of chromic acid vapours in the air varied from 0.1 to 

1.4 mg/m3 (Gomes, 1972).  In the vicinity of 3 different baths in a 

Swedish chromium plating factory, chromium concentrations ranged 

from 20 to 46 µg chromium (VI)/m3, while, at another factory, the 

exposure levels near all baths were below 1 µg/m3 (Lindberg et al., 



    Occupational exposure to chromium during welding has been 

analysed and the results published by several authors (Stern, 

1981).  Welding of metals using chromium and nickel electrodes 

require high temperatures that melt both the material welded and 

the electrode, producing a complex mixture of gases, oxides, and 

other compounds, the chemistry of which is determined by the 

technology, materials, and welding parameters used in each case 

(Lautner et al., 1978). Hexavalent chromium compounds were found in 

the respiratory zone of the welder at concentrations ranging from 

3.8 to 6.6 µg/m3 (Migai, 1975).  For the welding industry as a 

whole, the average exposure arising from welding is not homogeneous 

but depends on the type and conditions of the welding process 

(Stern, 1982). 


    In a cement-producing factory, the concentration of hexavalent 

chromium in the air in the work-place varied from 0.0047 to 0.008 

mg/m3.  The presence of chromium was explained by the fact that the 

lining of the kilns was composed of chrome-magnesium bricks 

containing 17 - 28% chromium compounds (Retnev, 1960).  Forty-two 

types of American cement were analysed for total chromium content 

and particularly for hexavalent chromium.  It was found that 

hexavalent chromium was present in 18 out of 42 samples in 

concentrations varying from 0.1 to 5.4 g/kg cement, while the total 

chromium content ranged from 5 to 124 g/kg (Perone et al., 1974).  

Analysis of 59 samples of Portland cement from 9 European countries 

showed that the contents of hexavalent chromium extractable with 

sodium sulfate varied from 1 to 83 g/kg of cement, while the total 

chromium contents ranged from 35 to 173 g/kg (Fregert & Gruvberger, 



4.3.2.  Dermal exposure


    Occupational dermal exposure can result in percutaneous 

absorption and in harmful effects on the skin (section 8.3.1), 

though the percutaneous absorption of chromium (III) sulfate has 

been questioned by Aitio et al. (1984). 


    Chromium, especially chromate, is the most common contact 

allergen and of great importance in occupational contact dermatitis 

(Thormann et al., 1979). 


    Chromium eczema occurred most frequently in building labourers 

followed by painters, galvanizers, machine drillers, metal-workers, 

graphic artists, and workers in the timber, chemical, leather, and 

textile industries (Polak et al., 1973).  This is likely to reflect 

the exposure to chromium compounds from a large number of every-day 

products (section 4.2.2).  The skin exposure to cement may be of 

particular importance as building labourers belong to the most 

affected group. 




5.1.  Absorption


5.1.1.  Absorption through inhalation  Animal studies


    Few animal studies have been performed to determine the 

absorption of chromium compounds via inhalation.  In one early 

study, mice and rats were exposed to chromium particulates in an 

inhalation chamber for various periods of time.  The concentrations 

of soluble chromium (CrO3) in air were between 1 and 2 mg/m3 for 

the mice and 2 and 3 mg/m3 for the rats.  The concentrations of 

soluble versus insoluble chromium in the lung tissue of the mice 

varied greatly.  The soluble chromium concentrations ranged from 

4.3 to 10.7 µg/kg dry tissue, after 100 weeks of exposure (Baetjer 

et al., 1959a). 


    The amount of chromium that is absorbed through inhalation 

depends on the size of the particles and droplets, on their 

solubility in body fluids, and on their reaction with the 

respiratory mucosa.  Particles greater than 5 µm in diameter 

(aerodynamic size) are deposited on the mucosal surface of the 

nasal membrane, trachea, and bronchi and are carried by the action 

of the cilia to the pharynx, where they are swallowed. Smaller 

particles and droplets, especially those below 2 mm in size, 

penetrate to the alveoli.  Particles and droplets of soluble 

compounds, such as hexavalent chromium compounds, are rapidly 

absorbed in the blood.  Insoluble particles, such as chromite, are 

taken up by macrophages and slowly cleared. Soluble materials that 

react with the constituents of the lung tissue, such as soluble 

trivalent compounds, are also cleared slowly.  Baetjer et al. 

(1959b) were the first to describe the differences in the clearance 

rates of soluble chromates and chromic chloride, when injected 

intratracheally into the lungs of animals.  The hexavalent chromate 

was more rapidly transported from the lungs to other tissues than 

the trivalent chromic chloride.  Ten minutes after injection, only 

15% chromium (IV) remained in the lung compared with 70% chromium 

(III).  After 60 days, the corresponding figures were 1.7% and 13% 

(Baetjer et al., 1959b).  Hexavalent chromium is taken up by the 

red blood cells in much larger quantities than trivalent chromium.  

This finding has been confirmed by Wiegand et al. (1984b) 

performing intratracheal instillation (Na251CrO4) studies on 

anaesthetized rabbits, as shown in Fig. 2.  Confirmation of the 

macrophage uptake of insoluble chromate was obtained by exposing 

hamsters to 0.5 - 1 mg chromic oxide dust/m3 for 4 h.  The median 

diameter of the particles was 0.17 µm.  Over 90% of the oxide was 

found in the macrophages (Sanders et al., 1971). 


FIGURE 2  Human data


    A mean chromium concentration of 0.22 mg/kg wet weight was 

found in the lung tissue of subjects from various locations in the 

USA, but there was no correlation between chromium levels in the 

lungs and those in the air (Schroeder et al., 1962). 


    A Committee of the National Research Council (US NAS, 1974a) 

concluded: "It is unlikely that the intake from air under ordinary 

conditions contributes significantly to the total intake of 

available chromium; the intake from the air is calculated to be 

less than 1 µg/day; but excessive exposure to airborne chromium 

does result in some increased intake". 


5.1.2.  Absorption from the gastrointestinal tract


    The absorption of ingested chromium compounds can be estimated 

by measuring the amount of chromium excreted in the urine, as 

almost all of intravenously injected chromium is excreted via the 

urine and only 2% is found in the faeces. Although a potential loss 

of endogenous chromium via the skin and its annexa has not yet been 

measured and quantified, it can be stated that this organ, as well 

as the gastrointestinal tract are of minor importance in the 

excretion of endogenous chromium.  The gastrointestinal tract is, 

of course, the major organ for the excretion of exogenous chromium. 


    When considering the gastrointestinal absorption of chromium, 

it is essential to recognize the substantial differences in the 

efficiency of absorption of trivalent and hexavalent compounds.  

These differences exist in both man and animals.  Many trivalent 

chromium compounds are so poorly absorbed that they have been used 

as faecal markers in man and animals.  The absorption of hexavalent 

chromium, administered orally, was higher in all species examined, 

but did not exceed 5% of the dose (Donaldson & Barreras, 1966).  No 

physiological regulation has yet been established for chromium 

absorption.  Animal studies


    The gastrointestinal absorption of chromate in rats has been 

reported to be between 3 and 6% of a tracer dose (MacKenzie et al., 

1958; Byerrum, 1961).  As in man, trivalent chromium compounds are 

less well absorbed in the rat, with reported efficiencies ranging 

from less than 0.5% (Visek et al., 1953) to 3% (Mertz et al., 

1965a).  Within the category of trivalent compounds, there are 

moderate differences in absorption, depending on the chemical form.  

Binding of the chromium ion to suitable ligands, such as certain 

organic acids, stabilizes the metal against precipitation in the 

alkaline milieu of the intestines and increases absorption 

efficiency by a factor of 3 - 5 times, compared with that for 

chromium chloride.  This has been shown for certain chelating 

agents (Chen et al., 1973), a yet unidentified small peptide 

complex isolated from yeast (Votava et al., 1973), and synthetic 

glucose tolerance factor (GTF), a dinicotinic-acid-glutathione-

chromium complex (Mertz et al., 1974).  Nothing is known about the 

interaction of chromium with the flora of the gastrointestinal 

tract.  Absorption of chromium chloride by ruminant species is 

similar to that in rats, with a mean efficiency of 0.76% (Anke et 

al., 1971); laying hens have been found to absorb almost 15% of a 

tracer dose of the element (Hennig et al., 1971).  Human studies


    Donaldson & Barreras (1966) studied the gastrointestinal 

absorption of hexavalent chromium by administering trace doses of 

Na251CrO4 orally to 6 volunteer patients, who were hospitalized, 

and by measuring the amount of radioactivity in the faeces and 

urine.  The mean urinary excretion, expressing the absorption 

efficiency, was 2.1 ± 1.5% of the dose given. Administration by 

jejunal infusion in 4 volunteers increased these values, suggesting 

reduction of the chromate to trivalent compounds by the acid 

content of the gastric juice. The same authors reported a mean 

absorption efficiency of only 0.5 ± 0.3% for trivalent chromium, 

administered as CrCl3 x 6H2O, with a range of 0.1 - 1.2%. 


    On the basis of the chromium content in diets (60 µg) and 

chromium excretion (0.22 µg) in healthy subjects, Anderson et al. 

(1983) calculated a minimum chromium absorption of about 0.4%. 

Increasing intake by supplementation with chromium (chromic 

chloride tablets, furnishing 200 µg chromium/day) led to an 

excretion of 0.99 µg, equivalent to 0.4% of the intake. 


    Aitio et al. (1984) investigated the intake and urinary 

excretion of chromium (III) in leather tanning workers.  The 

environmental concentrations were recorded as low, but chromium was 

present in air in the form of large droplets that were not 

collected by the standard air measurement technique. It was assumed 

that the large droplets were cleared by the upper respiratory tract 

and swallowed, and that the chromium in the droplets was absorbed 

from the gastrointestinal tract. A calculation showed that this 

would explain the urinary excretion levels.  No absorption of 

chromium through the skin was detected. 


    In a recent study, the minimum chromium absorption calculated 

on the basis of urinary-chromium excretion was about 0.4%.  

Increasing intake 5-fold, by chromium supplementation, led to a 

nearly 5-fold increase in chromium excretion, suggesting that the 

extent of absorption of supplemental inorganic chromium was similar 

to that from normal dietary sources (Anderson et al., 1983a). 


    A similar absorption for trivalent chromium of 0.69% was 

reported by Doisy et al. (1968) in healthy human subjects, 

regardless of age.  However, a group of 14 insulin-requiring 

diabetic patients absorbed 4 times as much of the chromium dose as 

the non-diabetic or maturity-onset diabetic subjects, as shown by 

elevated levels of 51chromium in blood plasma and urine (Doisy et 

al., 1971). 


5.2.  Distribution, Retention, Excretion


5.2.1.  Animal studies


    Most animal studies on chromium metabolism have been performed 

on rats.  From the site of intestinal absorption, chromium is taken 

up by plasma-protein fractions.  Small, physiological doses of 

51chromium have been shown to bind almost entirely to the iron-

binding protein, transferrin (Hopkins & Schwarz, 1964).  On the 

other hand, inhaled chromium (Glaser et al., 1984) was bound to 

albumin rather than to transferrin.  With larger quantities of 

trivalent chromium, non-specific binding to other proteins also 

occurred, but not to the red blood cells.  Visek et al. (1953) 

measured the effects of the different chemical forms of chromium on 

tissue distribution and found that soluble, chelated forms, such as 

acetate or citrate complexes, were cleared quite rapidly, in 

contrast with colloidal or protein-binding forms (chromite, chromic 

chloride), which have a great affinity for the reticulo-endothelial 

system (bone marrow, liver, spleen), and clear more slowly.  The 

blood clearance of hexavalent chromium, such as chromate, was slow, 

because of irreversible binding within the red blood cells.  Tissue 

distribution of 51chromium, administered in nanogram doses to rats 

was studied by Hopkins (1965).  As in the preceeding studies, the 

element accumulated in bone, spleen, testes, and epididymis; much 

less was retained in the lungs, brain, heart, and pancreas. This 

obvious difference in chromium distribution between man and rats is 



    As in man, trivalent 51chromium in the rat was rapidly cleared 

from the blood, after absorption, and was retained by the tissues 

(Mertz et al., 1965a).  These tissue stores, labelled with 

51chromium chloride, administered orally or intravenously, were not 

immediately available for specific physiological functions.  For 

example, 51chromium, administered as CrCl3 x 6H2O to pregnant rats, 

was not transported into the embryos (Mertz et al., 1969), nor did 

any 51chromium appear in the blood in response to glucose or 

insulin injections (Mertz & Roginski, 1971).  The fact that fetal 

chromium concentrations are low, when the pregnant rats are fed a 

low-chromium Torula yeast diet, and increase when a high-chromium 

natural stock ration is fed, indicates that placental transport and 

possibly, the acute chromium response depend on a special form of 

chromium, which is different from chromium chloride.  It is 

possible, but has not yet been proved, that this form is the 

dinicotinic acid-glutathione-chromium complex, known as glucose 

tolerance factor.  Yeast extracts containing this factor labelled 

with 51chromium have been shown to cross the placenta (Mertz et 

al., 1969) and, in preliminary studies, to furnish chromium for the 

acute chromium response (Mertz & Roginski, 1971). 


    With reference to interactions between chromium and other trace 

elements, competition with iron by way of their common carrier 

(transferrin) has been suggested in rats (Hopkins & Schwarz, 1964) 

and in human beings (Sargent et al., 1979). Goncharov (1968) 

reported a close interaction between chromium and dietary iodine.  

In iodine-deficient white rats, addition of chromium to the diets 

in amounts supplying from 0.6 to 600 µg/animal per day stimulated 

thyroid function, as indicated by morphological and functional 

changes. Conversely, chromium, in all but the lowest dose, 

decreased thyroid function in animals receiving adequate iodine 

levels. This relation is in agreement with epidemiological data 

from the USSR (Goncharov, 1968). 


5.2.2.  Human data  Concentration in tissues, blood, urine, and hair

including possible biological indicators of exposure


    (a)   Tissues


    The most comprehensive survey of tissue-chromium concentrations 

is that of Schroeder et al. (1962), who carried out a 

spectrographic analyses on 20 - 39 samples for each autopsy tissue, 

all of which had been carefully collected to avoid extraneous 

contamination.  The following results were obtained (mean values in 

mg/kg ash) for a group of subjects who had died between the ages of 

30 and 40 years: lung, 15.6; aorta, 9.1; pancreas, 6.5; heart, 3.8; 

testes, 3.1; kidney, 2.1; liver, 1.8; spleen, 1.7.  In all tissues, 

except for the lungs there was a rapid decline in chromium 

concentrations from time of birth to the age of 10 years, followed 

by a more gradual decrease to the age of 80 years.  It cannot be 

stated with certainty whether the decline is an expression of a 

physiological mechanism or of a dietary deficiency.  The lungs lost 

their initially high chromium levels (85.2 mg/kg ash) up to the age 

of 20 years (6.8 mg/kg); subsequently, the concentrations increased 


to between 20 and 38 mg/kg.  This discrepancy demonstrates that the 

chromium in lungs is not in equilibrium with the general pool.  The 

decline of chromium in the aorta, quite pronounced in subjects in 

the USA, was much less dramatic in the aortas from subjects of 

other countries (Schroeder et al., 1970). 


    Mancuso & Hueper (1951), as well as Baetjer et al. (1959b), 

found concentrations of chromium in the lungs of former chromate 

workers that were several orders of magnitude higher than those in 

control subjects.  In a study on 16 chromate workers, including 11 

with lung cancer, Baetjer et al. (1959b), using a colorimetric 

method, observed a median concentration of water- and acid-soluble 

chromium in the lung of 70 mg/kg dry weight and a median 

concentration of acid-insoluble chromium of 17 mg/kg.  The chromium 

concentration did not differ between cancer cases and non-cancer 

cases.  The tissue specimens were obtained 0 - 23 years after the 

termination of occupational exposure, which had lasted 1.5 - 42 

years.  With the use of emission spectrometry and atomic absorption 

spectrophotometry, Hyodo et al.  (1980) found a chromium content of 

3.6 mg/kg wet weight in the lung in a male smoker with lung cancer, 

who died 10 years after employment for 30 years in a chromate-

producing plant.  The concentration in other tissues ranged from 

0.05 (bone marrow) to 1.5 mg/kg (suprarenal gland).  In five 

unexposed controls, lung concentrations ranged from 0.09 to 0.88 

mg/kg; concentrations in other tissues ranged from 0.003 (kidney) 

to 0.156 mg/kg (suprarenal gland).  The ratio of hexavalent to 

total chromium in the lungs was 29% in the worker and 22.7 ± 10.6% 

(mean ± SD) in the controls. 


    Brune et al. (1980) gave tissue concentrations for chromium and 

other metals in the lung, liver, and kidney of 20 deceased copper 

smelter workers, who had retired 0 - 19 years prior to death, and 

of a control group (8 subjects).  Tissue analysis was carried out 

using neutron activation analysis as well as atomic absorption 

spectrophotometry, and included a comparison with certified 

reference samples (National Bureau Standards, bovine liver).  In 

the controls, the concentrations ranged from below detection (0.003 

mg/kg wet weight) to 0.07 mg/kg in kidneys and 0.11 mg/kg in liver.  

There was no marked difference between the chromium contents of 

these 2 tissues and those in the exposed workers.  On the other 

hand, the lung concentrations were between 3 and 4 times higher in 

the workers than in the controls (median levels, 0.29 and 0.08 

mg/kg, respectively). 


    Chromium determinations were carried out on lung and kidney 

samples of 45 autopsies from the Northern Bavaria area (Federal 

Republic of Germany) (Zober et al., 1984).  The analyses were 

carried out using electrothermal AAS after wet oxidative digestion.  

Median values of 0.097 mg/kg wet weight (range, 0.0006 - 1.230 

mg/kg) in lung tissue and 0.0096 mg/kg wet weight (range, 0.0002 - 

0.690 mg/kg) in kidney were found. 


    Very limited data are available on chromium levels in tissues 

other than those referred to above.  Shmitova (1978) estimated 

chromium levels in fetal and placental tissues (abortive material), 


derived on the 12th week of pregnancy, and found 92.8 and 30 µg 

Cr/kg tissue, respectively. 


    It can be concluded that chromium may be retained in the lungs, 

several years after the termination of occupational exposure.  

However, it is not known whether this observation has any 

biological relevance to the appearance of lung cancer.  In this 

context, it is of interest to note that chromium is retained in the 

human lung for a relatively long period, even without occupational 



    (b)   Blood


    The values reported by various investigators for chromium 

concentrations in the blood of unexposed human beings range from 

0.2 to 70 µg/litre in serum and plasma and 5 to 54 µg/litre in red 

blood cells (US EPA, 1978).  Insufficient evidence is available to 

state whether the blood values in the normal population are 

influenced by concentrations in the ambient air.  The most 

extensive determination of blood-chromium levels in chromate 

workers was made by Mancuso (1951).  Blood values during exposure 

varied from 5 to 170 µg/litre and from 10 to 140 µg/litre, 74 days 

after work ended.  No decrease in blood-chromium levels was found, 

even after 74 days without exposure. 


    Because of a selective affinity of hexavalent chromium for the 

erythrocyte, substantially increased environmental exposure to 

chromates is reflected in an increased ratio of the hexavalent 

chromium level in red blood cells to that in plasma.  Baetjer et 

  1. (1959a) found the following concentrations in 3 exposed 

chromate workers: blood cells, 30, 54, and 140 µg/litre; plasma, 0, 

20, and 17 µg/litre, respectively.  In the absence of exposure to 

chromate, the chromium concentrations in erythrocytes and plasma, 

as serum, were nearly identical (Paixao & Yoe, 1959).  Chromium 

(VI) is incorporated into human red blood cells and remains there 

over a long period of time (Wiegand et al., 1985), since the 

approximate lifetime of human red cells is about 100 days. Exposure 

to 2 mg trivalent chromium/day, for 3 months, resulted in an 

increased concentration  (0.2 mg/kg) in the red cells of 5 human 

males, compared with 0.11 mg/kg in 5 controls without supplement 

(Schroeder et al., 1962).  However, later studies did not show any 

increase in chromium concentrations in red cells, following 

exposure to trivalent chromium (Beyersmann et al., 1984; Wiegand et 

al., 1985).  Monitoring of red blood cell-chromium may be a useful 

indicator of exposure to hexavalent, but not to trivalent, 



    Most of the later studies show that the true chromium 

concentration in the plasma or serum of healthy subjects is of the 

order of 1 µg/litre or less (Guthrie et al., 1978; Versieck et al., 

1978).  Seeling et al. (1979) determined chromium in serum and 

plasma using flameless AAS.  This study was supported by measuring 

a standard reference material (National Bureau of Standards, 1569 

brewer's yeast, reference data: 2.12 ± 0.05 mg/kg, measured data: 

2.3 ± 0.2 mg/kg).  The chromium levels in serum ranged from 0.7 to 

2.2 µg/litre and in plasma from 1 to 1.5 µg/litre (central 

parameters of a long normal distribution). 


    Pooled serum samples of 6 healthy Finnish volunteers were 

studied by Kumpulainen et al. (1983).  A mean value of 0.11 ± 0.05 

µg chromium/litre (range, 0.06 - 0.20) was found. Nomiyama et al. 

(1980b) analysed 20 blood samples of Japanese subjects, using 

direct flameless ASS, and reported a value of 2.9 ± 1.7 µg 

chromium/litre whole blood. 


    Zober et al. (1984) analysed the blood of 45 autopsied subjects 

from the Northern Bavaria area (Federal Republic of Germany).  A 

median chromium concentration of 2.8 µg/litre of postmortem blood 

(range, 0.20 - 24 µg/litre) was found, the value was not influenced 

by age or sex. 


    A reference material for chromium, bovine serum (RM 8419) is 

available from the National Bureau of Standards, Washington DC, 



    (c)   Urine


    Chromium concentrations in the urine of non-occupationally 

exposed subjects have been reported to range from 1.8 to 11 

µg/litre (Imbus et al., 1963).  Except for exposed persons and 

juvenile diabetic patients, the reported values for daily chromium 

excretion in urine (Table 9) do not differ as much as those for 

blood.  In later studies, such as that of Guthrie et al. (1979), a 

method of flameless atomic absorption was used in which it was 

possible to correct for spectral interference (Zander et al., 

1977).  Such interference was difficult to eliminate with earlier 

methods (Guthrie et al., 1978).  Urine samples from 189 Japanese 

volunteers, aged 10 - 80 years, in 4 pollution-free areas, were 

analysed for chromium by Nomiyama et al. (1980a), using direct 

flameless AAS.  The average level was 0.4 ± 0.37 µg/litre (X ± SE) 

or 0.47± 0.42 mg/kg creatinine.  Urinary chromium tended to be 

higher in males than in females and to decrease with age, but the 

differences were not significant.  Using electrothermal AAS, the 

urinary excretion of various metals in non-occupationally exposed 

adults was measured by Schaller & Zober (1982).  For smokers, a 

median value of 1.6 µg chromium/litre was found (non-smoker: 1.4 µg 

chromium/litre).  Commercially available urine samples were used 

for quality control (Angerer et al., 1981).  Although a "normal" 

level of chromium excretion for healthy, unexposed persons cannot 

yet be established with certainty, such a level may be less than 1 



    Several investigators have measured urinary-chromium excretion 

in exposed workers.  In a study on chromate workers, the urine 

values ranged from 5 to 380 µg chromium/litre during exposure and 

from 10 to 54 µg chromium/litre, 74 days after the end of exposure 

(Mancuso, 1951).  No relationship was evident between the urine 

levels and the weighted average number of years of exposure.  In 

every case where urine values were recorded, both during, and 74 

days after the end of, exposure, the chromium concentrations 

decreased with time away from exposure. 


    A study of 12 workers in a galvanizing plant in the Federal 

Republic of Germany showed an average concentration of chromium in 

urine of 9.5 µg/litre (range, 1.4 - 24.6 µg/litre) compared with a 

value of 1.8 ± 1.1 µg/litre in 60 unexposed workers (Schaller et 

al., 1972).  Gylseth et al. (1977) investigated a group of 14 

welders exposed to about 0.05 mg chromium/m3 air, and reported a 

urinary chromium concentration of approximately 40 mg/litre.  At 

the same exposure level, Tola et al. (1977) found a concentration 

of 30 mg chromium/kg of creatinine in the urine.  In both of these 

studies, there was a correlation between recent exposure to 

airborne chromium and chromium concentrations in urine.  In the 

study by Tola et al. (1977), it was shown that the water-soluble 

fraction of airborne chromium was better correlated with the 

concentration excreted in the urine than with total chromium.  It 

was also shown that the water-soluble fraction consisted mainly of 

hexavalent chromium. 


Table 9.  Daily chromium excretion in urine


Subjects           Number Excretion     Range Reference

                           (µg/day)       (µg/day)

                           (mean ± SD)


Adult males        2 0.72a     0.58 - 0.86 Schroeder et al.



Adult males, fed   3 31.0a     20.8 - 46.5 Schroeder et al.

2 mg trivalent,                                        (1962)

chromium/day for         

3 months                 


Normal adults      16 13 ± 6     4 - 24 Voelkl (1971)

Chromate workerb           16 000


Normal adults      60 1.6 ± 1.1                 Schaller et al.



Galvano-technical  12 9.7 ± 6.6     1.4 - 24.6 Schaller et al.

workers                                                (1972)


Normal young       20 8.4 ± 5.2                 Hambidge (1974)



Normal children,   18 5.5 ± 2.9                 Hambidge (1974)

8 years old


Insulin-dependent  7 19.2 ± 18.9                 Hambidge (1974)

diabetic children,       

11 years old             


Young women        9 7.2 ± 1.2     5.9 - 10.0 Mitman et al.



Adult males        12 0.8 ± 0.4     0.4 - 1.8 Guthrie et al.




Table 9.  (contd.)


Subjects           Number Excretion     Range Reference

                           (µg/day)       (µg/day)

                           (mean ± SD)


Adult males        91 0.48 ± 0.41a   0.42 - 0.53 Nomiyama et al.



Adult females      98 0.34 ± 0.31a   0.22 - 0.43 Nomiyama et al.



Adult males        48 0.20 ± 0.01a   0.05 - 0.58 Anderson et al.



Adult females      28


Adult males        27 0.17 ± 0.10                 Anderson et al.



Adult females      15 0.20 ± 0.12                 Anderson et al.



Adult males and    299 0.80 ± 0.6a    0.4 - 2.1 Fang (1983)



Normal adults      10 0.11 ± 0.05a   0.06 - 0.20 Kumpulainen et al.



Normal adultsc     10 4.9     0.10 - 14.2 Zober et al.



a   Data calculated as µg/litre urine.

b   Tanner, suffering from an acute ulceric gasteroenterocolitis.

c   Samples taken post-mortem from autopsies. Original values are related

    to mass (kg) instead of volume (litre).

    Lindberg & Vesterberg (1983a) measured airborne, and urinary-

chromium levels among platers.  Concentrations of chromium in urine 

of < 5 µg/litre occurred when the time-weighted average values of 

exposure were about or below 2 µg/m3 air.  Severe damage to the 

nasal septum and effects on lung function have not been found at

levels lower than this. It was shown that post-shift urinary-

chromium determinations could be used to monitor exposure in this 

occupational group. 


    The urinary-chromium excretion and chromium clearance in 22 

welders, who had been exposed to airborne hexavalent chromium (5 - 

150 µg/m3) during 2 - 40 years (mean working time, 18.9 years) were 

measured by Mutti et al. (1979).  The method used was flameless 

atomic absorption spectrometry.  A highly significant correlation 

was detected between the ratio of urinary-chromium to creatinine 

and the airborne chromium concentration in the workplace, with 

excretions ranging from 5.3 ± 3.7 to 33.3 ± 6.9 mg chromium/kg 

creatinine in slightly exposed and heavily exposed welders, 


respectively.  The authors also reported an increase in chromium 

clearance with increasing body burden of chromium, which indicates 

that high urinary-chromium excretion may be caused by previous high 

exposure as well as by current exposure. 


    Baseline data for chromium excretion in unexposed subjects in 

the report by Mutti et al. (1979) are approximately 10 times higher 

than the values recently proposed and generally accepted as normal.  

However, there is reason (section 2.2.2) to accept relative 

differences in analytical results in studies by one author using 

one method, even if the absolute values reported may be questioned. 


    To test whether chromium excretion is also associated with 

exercise-induced increases in glucose utilization, the urinary 

chromium excretion, serum glucose, insulin, and glucagon of 9 male 

runners (23 - 46 years old) were evaluated by Anderson et al. 

(1982a).  The mean urinary-chromium concentration was increased 

nearly 5-fold, 2 h after running; excretion of sodium, potassium, 

and calcium was unchanged.  These data demonstrate an increase in 

chromium excretion with exercise-induced increase in glucose 



    (d)   Milk


    The chromium concentration was determined in 261 samples of 

breast milk collected by manual expression from 45 American women.  

Chromium levels were measured in whole, liquid milk by graphite-

furnace AAS, using the method of standard additions. The mean 

chromium content of the breast milk samples was 0.30 µg/litre.  The 

range of individual values was 0.06 - 1.56 µg/litre and did not 

change significantly with duration of lactation (Casey & Hambidge, 

1984).  Kumpulainen et al. (1983) analysed frozen samples of pooled 

breast milk taken from women in different stages of lactation and 

obtained from the Milk Bank of the Children's Hospital of Helsinki.  

The mean chromium content ± SD was 0.49 ± 0.067 µg/litre (range, 

0.37 - 0.57 µg/litre). 


  (e)   Hair


    Hair-chromium concentrations in children during the first 6 

months of life were significantly higher than at any other age 

(Hambidge & Baum, 1972); they declined from an initial value of 

1493 µg/kg to an average of 412 µg/kg at 2 - 3 years.  Hambidge 

(1971) compared the chromium concentration in the hair of 15 

newborn babies and that of their mothers: in only one case was the 

chromium level in the mother's hair higher than that in the newborn 

baby.  Chromium levels were significantly lower than those 

mentioned above in 50 Turkish women and their newborn babies (203 

and 119 µg/kg, respectively) and only 12 newborn babies were found 

to have higher concentrations than their mothers, suggesting 

suboptimal chromium status (Gürson, 1977).  Hair appears to reflect 

the nutritional chromium status of groups.  The hair-chromium level 

is significantly lower in parous women than in nulliparae (Hambidge 

& Rodgerson, 1969; Mahalko & Bennion, 1976) and in diabetic 

children compared with normal controls (Hambidge et al., 1968).  It 

is low in adult-onset diabetic adults (Benjanuratra & Bennion, 


1975).  These findings are in agreement with the expected changes 

in chromium balance during pregnancy and in diabetes.  Dynamic aspects of metabolism and the influence of

pathological states


    Once chromium is absorbed into the organism, it clears rapidly 

from the blood stream and is excreted or taken up by the tissues.  

In a clinical study, Sargent et al. (1979) detected a 4-

compartment-type clearance from blood, with mean half-times of 13 

min, 6.3 h, 1.9 days, and 8.3 days.  However, the disappearance 

from 3 tissue compartments was much slower, with half-times of 

0.56, 12.7, and 192 days.  The half-times for blood 3-compartment 

clearance in rats (Hopkins, 1965) were calculated to be 0.56, 5.33, 

and 57 h (Withey, 1983). 


    Whether any organ is specifically responsible for the storage 

and release of the "metabolically responsive" chromium is not 

known.  The "metabolically responsive" chromium in blood is defined 

as the fraction that increases acutely in response to an elevation 

of blood-glucose or blood-insulin levels.  It is believed that this 

chromium increment interacts with the increased insulin secreted in 

response to a glucose load, to facilitate the action of the hormone 

on the insulin receptors of the insulin-sensitive cells. 


    In young, healthy subjects, but not in elderly subjects and 

diabetic patients, an oral glucose load or the injection of insulin 

results in a sudden increase in serum- or plasma-chromium 

(Glinsmann et al., 1966; Levine et al., 1968; Hambidge, 1971; Behne 

& Diel, 1972; Liu & Morris, 1978).  This increase may appear 30 

min, or as late as 120 min, after the challenge; much of the 

chromium responsible for the increase is subsequently lost in the 

urine.  Lack of this increase, also termed "relative chromium 

response", is often associated with impaired glucose tolerance, 

indicative of chromium deficiency.  It should be noted that, when 

the glucose load was given intravenously (Pekarek et al., 1975) to 

healthy volunteers, the serum-chromium level decreased rapidly, 

while the blood-glucose level increased.  Supplementation with 

chromium chloride or high-chromium yeast extracts for several weeks 

resulted in the reappearance of the relative chromium response and 

improvement of glucose tolerance (Glinsmann et al., 1966; Liu & 

Morris, 1978).  These findings support the conclusion that the 

"relative chromium response" measured during a glucose or insulin 

tolerance test may serve as an indicator of the adequacy of 

metabolically responsive chromium. 


    Much of the chromium increment secreted into the blood stream 

in response to glucose or insulin is subsequently lost in the 

urine.  Hambidge (1971) observed greatly increased urinary-chromium 

excretion in 2 diabetic children after insulin therapy had begun, 

compared with the excretion in the same children before insulin 

treatment.  It is not known whether the increased urinary loss of 

chromium is compensated for by an increase in absorption efficiency 

from the intestines.  Hambidge et al. (1968) reported significantly 

lower chromium concentrations in the hair of diabetic children 

compared with normal children, and Morgan (1972) found that 


the chromium contents in the livers of 31 diabetic adults at 

autopsy were lower than those in 24 control livers from non-

diabetic persons (8.57 versus 12.7 mg/kg ash;  P = 0.05). 


    On the other hand, Doisy et al. (1971) demonstrated greatly 

increased intestinal absorption, together with elevated chromium 

excretion, in 14 insulin-dependent diabetic patients administered 

51CrCl3 x 6H2O, orally.  It is not known whether the greater 

absorption efficiency is adequate to compensate for the increased 

urinary losses; the decreased chromium concentrations in hair and 

liver, discussed above, suggest that a negative balance may prevail. 


    Several other pathological conditions affect chromium 

metabolism.  Sargent et al. (1979) detected significantly less 

retention of intravenously administered 51chromium in 11 patients 

with haemochromatosis compared with 5 normal controls.  This may be 

related to the high saturation with iron of transferrin, which is 

also the carrier protein for newly absorbed chromium. 


    Chronic ischaemic heart disease also affects chromium 

metabolism.  Neiko & Del'va (1978) observed a significantly 

increased urinary-chromium loss, greater by a factor of 1.5 - 1.6 

than that of normal controls, in 65 heart patients.  The urinary-, 

and to a lesser extent, the faecal-chromium loss increased 

progressively with increasing severity of signs and symptoms and 

resulted in a negative chromium balance in the post-infarct state.  

The balance became positive again on discharge from the hospital 

after medical treatment. 


    Acute infections also appear to influence chromium metabolism.  

Pekarek et al. (1975) measured glucose tolerance, and insulin and 

chromium levels in human volunteers, before and after infection 

with the benign sandfly fever virus. Impaired glucose tolerance and 

a significantly increased insulin response to a glucose load, 

observed at the height of the infection, were accompanied by very 

significantly depressed serum-chromium levels (0.5 µg/litre, 

compared with 1.4 µg/litre before infection;  P < 0.05) In 

contrast with the sharp decline in serum-chromium following the 

intravenous injection of glucose in the healthy state observed by 

these authors, the depressed serum-chromium levels declined very 

little during the glucose tolerance test at the height of 

infection.  The mechanism of the changes in chromium metabolism in 

heart disease and sandfly fever is not clear. Of great potential 

importance is the unanswered question of whether the observations 

described here reflect an increased chromium requirement in the 

patients or a normal reaction to various forms of stress. 


    The information on the dynamic aspects of chromium metabolism 

in animals is limited and should be considered in connexion with 

the more detailed studies on human subjects. Diabetes, induced in 

rats by the injection of streptozotocin, affected the tissue 

distribution of injected 51CrCl3.  Sixteen days after injection of 

streptozotocin, 51CrCl3 was injected into 5 diabetic rats and 6 

normal controls and the 51Cr content measured 5 days later.  The 

serum of the diabetic rats contained more than 3 times the 51Cr 

activity found in the controls (0.24 versus 0.07% of the injected 


dose  P < 0.01). Significant differences were also detected in the 

distribution of 51Cr in the subcellular fractions of the liver;  in 

the diabetic tissue, 51Cr activity was higher in the nuclear and 

supernatant fractions ( P < 0.01) and lower in mitochondria and 

microsomes ( P < 0.05).  The mechanism responsible for these 

changes is not known (Mathur & Doisy, 1972). 


5.3.  Influence of Chemical Form


    The diverse biological effects of chromium on living organisms 

cannot be understood without knowledge of the chemical and physical 

forms in which the element is present. As stated earlier, the 

metallic state (zero valence) is biologically inert, the trivalent 

state represents the essential element chromium, and the hexavalent 

state is of concern to the toxicologist.  Compounds of trivalent 

chromium are poorly absorbed, whereas those of the hexavalent state 

easily penetrate physiological barriers, such as cell membranes.  

Hexavalent chromium compounds are easily reduced by living matter, 

but oxidation of trivalent to hexavalent chromium does not occur in 

the organism. 


    The physical form of hexavalent compounds (such as particle 

size) and chemical properties (such as solubility) determine 

metabolic pathways after inhalation and, therefore, health effects.  

There is an equally strong influence of the chemical form of 

trivalent chromium on metabolism and health effects.  When chromium 

is bound to water or small anions (e.g., CrCl3 x 6H20), it 

precipitates in the neutral or alkaline milieu of the body fluids.  

When it is bound to ligands, such as organic acids, the element is 

light in solution and is available for intestinal absorption.  The 

forms in which trivalent chromium occurs in nature are not really 

known.  Plants probably contain chromium complexes with organic 



    The biological availability of chromium compounds in foods is 

of great nutritional importance, but is poorly defined. One 

compound or a group of closely related compounds, glucose tolerance 

factor, has been isolated from yeast and shown to be more active 

than chromium chloride in genetically diabetic mice and in the  in 

 vitro potentiation of the action of insulin on rat epididymal fat 

tissue (section  It has been identified as a dinicotinic-

acid glutathione complex, but the exact stereochemical structure is 

not yet known (Toepfer et al., 1977).  It has been postulated, but 

not proved, that this factor is the active form of chromium within 

the organism. 




    The environmental effects of chromium as a pollutant have been 

reviewed by US EPA (1978), Anderson (1982), and EIFAC (1983).  

Various effects have been reported, but, because of the presence of 

other chemicals, it remains doubtful whether chromium alone is 

responsible for the effects observed.  Data are available on 

microorganisms, plants, and aquatic organisms. 


6.1.  Microorganisms


    Most microorganisms (protozoa, protophyta, fungi, algae, 

bacteria) are able to absorb chromium.  The active uptake of 

chromate by the sulfate transport system has been shown in 

 Neurospora crassa  (Roberts & Marzluf, 1971).  No distinction has 

been made between ab- and adsorption in other studies (e.g., algae) 

(Calow & Fletcher, 1972), and it has not yet been shown that 

chromium is an essential element for microorganisms.  In general, 

toxicity for most microorganisms occurs in the range of 0.05 - 5 mg 

chromium/kg of medium.  The internal concentration of chromium 

depends on the species.  In most groups of microorganisms, it 

ranges between the levels of 0.6 mg dry weight present in one litre 

of sample of microplankton from Monterey Bay, California, USA, and 

21.4 mg/litre phytoplankton collected in the Pacific Ocean (Martin 

& Knauer, 1973). 


    Trivalent chromium is less toxic than hexavalent.  The main 

features are inhibition of growth (at concentrations greater than 

0.5 mg/litre in  Chlorella cultures) (Nollendorf et al., 1972) and 

inhibition of various metabolic processes, such as photosynthesis 

or protein synthesis (US EPA, 1978). 


    The toxicity of chromium for soil bacterial isolates was 

studied by measuring the turbidity of liquid cultures supplemented 

with hexavalent chromium and trivalent chromium. Gram-negative 

bacteria were more affected by hexavalent chromium (1 - 12 mg/kg) 

than gram-positive bacteria.  Toxicity due to trivalent chromium 

was not observed at similar levels. The toxicity of low levels of 

hexavalent chromium (1 mg/kg) indicates that soil microbial 

transformations, such as nitrification, may be affected (Ross et 

al., 1981). 


6.2.  Plants


    Although chromium is present in all plants, it has not been 

proved to be an essential element for plants.  Most substances, 

including chromium, can be absorbed through either the root or the 

leaf surface.  Several factors affect the availability of chromium 

for the plant (Black, 1968), including the pH of the soil, 

interactions with other minerals or organic chelating compounds, 

and carbon dioxide and oxygen concentrations. 


    Little chromium is translocated from the site of absorption; 

however, the chelated form is transported throughout the plant 

(Verfaillie, 1974). 


    Chromium in high concentrations can be toxic for plants, but 

Yopp et al. (1974) stated that there was no specific pattern of 

chromium intoxication. 


    During the smelting of chromite, considerable quantities of 

waste are produced, which contain soluble chromates.  When combined 

with a high pH, Gemmell (1973) showed an inhibition of germination 

and growth in white mustard plants  (Sinapis alba) growing on waste 

heaps.  Covering the waste with a 25-to 30-cm layer of granular-

free-draining subsoil followed with layers of soil, peat, or sewage 

sludge was shown to be the best revegetation technique (Gemmell, 



    The main feature of chromium intoxication is chlorosis, which 

is similar to iron deficiency (Hewitt, 1953). 


    Soybeans, treated in nutrient culture containing 0 - 5 mg 

hexavalent chromium/litre showed decreased uptake of calcium, 

potassium, phosphorus, iron, and manganese (Turner & Rust, 1971).  

Death of plants occurred within 3 days of treatment with 30 or 60 

mg chromium/litre. 


    A reduction in leaf dry weight occurred after treatment with 

0.01 mg hexavalent chromium/litre (Rediske et al., 1955).  Chromium 

affects the carbohydrate metabolism, and the leaf chlorophyll 

concentration decreased with increasing hexavalent chromium 

concentration (0.01 - 1 mg hexavalent chromium/litre) (Rediske, 

1956).  Hexavalent chromium appears to be more toxic than trivalent 

chromium (Hewitt, 1953; Stanley, 1974; Verfaillie, 1974).  At 

present, no data are available concerning the mechanism of action 

or the dose-dependent pattern of chromium intoxication. 


6.3.  Aquatic Organisms


    More studies have been performed with aquatic species than with 

free-living (non-parasitic) animals.  Depending on the species, 

chromium can be less toxic for fish in warm water, but marked 

decreases in toxicity are found with increasing pH or water 

hardness; changes in salinity have little if any effect on its 

toxicity.  Chromium can make fish more susceptible to infection; 

high concentrations can damage and/or accumulate in various fish 

tissues and in invertebrates such as snails and worms.  

Reproduction of  Daphnia was affected by exposure to 0.01 mg 

hexavalent chromium/litre (EIFAC, 1983).  Numerous other factors 

influence the availability of chromium and, therefore, its 

toxicity.  These include the presence of other minerals and organic 

pollutants, and the temperature of the environment; this has been 

shown in mice (Nomiyama et al., 1980a). 


    Hexavalent chromium is accumulated by aquatic species by 

passive diffusion (US EPA, 1978).  Ecological factors, in the 

abiotic and living environment, are involved in this process, which 

varies according to the sensitivity of different species.  The 

physiological state and activity of the fish also affect 

accumulation (Reichenbach-Klinke, 1977, 1980). Kittelberger (1973) 

analysed the organs and tissues of the roach  (Leuciscus rutilus)


from the river Rhine and found that concentrations of chromium in 

the spleen, bronchi, and intestine (between 30 and 37.5 mg/kg) were 

10 - 30 times higher than those in the heart, skin, muscle, and 



    LC50s are listed in Table 10 for hexavalent and trivalent 

chromium compounds in the aquatic environment. 


Table 10.  The toxicity of chromium for fresh-water organisms 

(expressed as 50% mortality)a


Compound    Category   Exposure Toxicity range  Most

                                        (mg/litre)      sensitive



hexavalent  invertebrate  acute 0.067 - 59.9    scud

chromium                  long-termb -     -


            vertebrate    acute 17.6 - 249      fathead minnow

                          long-term     0.265 - 2.0   rainbow trout


trivalent   invertebrate  acute 2.0 - 64.0      cladoceran

chromium                  long-term 0.066     cladoceran


            vertebrate    acute 33.0 - 71.9     guppy

                          long-term     1.0   fathead minnow


a  From: US EPA (1980).

b  No data available.


    In general, invertebrate species, such as polychaete worms, 

insects, and crustaceans are more sensitive to the toxic effects of 

chromium than vertebrates, such as some fish (Mathis & Cummings, 

1973).  The lethal chromium level for several aquatic and 

nonaquatic invertebrates has been reported to be 0.05 mg/litre (US 

NAS/NAE, 1972). 


    EIFAC (1983) reviewed the literature on the occurrence and 

effects of chromium in fresh water and proposed tentative water-

quality criteria that distinguish between salmonid and non-salmonid 

waters.  To protect salmonid waters, the mean aqueous concentration 

of "soluble" chromium should not exceed 0.025 mg chromium/litre, 

and the 95 percentile should not exceed 0.1 mg chromium/litre.  

However, more stringent values may be necessary in very soft, acid 

waters, and less stringent values in alkaline waters. 




7.1.  Nutritional Effects of Chromium


    The criteria for an essential nutrient have been defined in 

different ways by different authors, but all definitions postulate 

that a reduction in the total daily intake of the nutrient below a 

certain level must consistently induce signs of deficiency, and 

that the supplementation of the daily intake above this level must 

prevent and cure the deficiency signs.  Chromium deficiency has 

been produced experimentally in mice, rats, and squirrel monkeys, 

and the full reversal of the deficiency signs by the oral 

administration of chromium has been demonstrated in rats (Mertz, 

1969).  For these reasons, chromium must be considered an essential 

micro-nutrient.  It is physiologically active in the trivalent 

oxidation state at concentrations of approximately 100 µg/kg diet. 


7.1.1.  Effects of deficiency on glucose metabolism


    Semipurified rations, containing Torula yeast as the source of 

protein, were fed to groups of 10 male Sprague Dawley rats at 

weaning, and intravenous glucose tolerance tests were performed by 

injecting 1250 mg glucose/kg body weight and measuring the 

subsequent decline in blood-glucose levels.  The rate of glucose 

disappearance can be calculated from the straight line plot of log 

increment glucose (excess of glucose at any time (t) over fasting 

glucose), versus time.  The disappearance constant k is expressed 

as % decline of the increment glucose per min; it is a measure of 

the efficiency of glucose utilization.  In weaning rats, the rate 

constant was found to decline, within 3 weeks or less, from an 

average of 4%/min to 2.6%/min in animals fed the Torula yeast diet, 

but not in animals administered a diet in which 4 or 8% of Torula 

yeast was replaced by an equal amount of brewer's yeast.  This 

observation suggested that brewer's yeast, but not Torula yeast, 

contained an unknown substance necessary for the maintenance of 

normal glucose tolerance.  Because the only known effect of the 

substance was that on glucose tolerance, it was named "Glucose 

Tolerance Factor" (GTF) (Mertz & Schwarz, 1959).  GTF was extracted 

from brewer's yeast and pork kidney powder, concentrated and 

purified, and its active ingredient was identified as trivalent 

chromium (Schwarz & Mertz, 1959).  Chromium in the form of most 

common complexes (except for very stable ones) cured the impairment 

of glucose tolerance in deficient rats, either as one oral dose of 

200 µg/kg body weight, or as an intravenous (iv) injection of 2.5 

µg/kg body weight.  Chromium in the diet also prevented the 

impairment of glucose tolerance. 


    In order to produce more pronounced deficiencies of chromium 

and other trace elements, Schroeder et al. (1963) constructed a 

special animal house on a mountain top in Vermont, USA, far removed 

from traffic and industry.  The interior was specially coated with 

organic resins to reduce any metallic exposure.  Air was introduced 

through special filters, and strict practices were enforced to 

avoid the introduction of dust and dirt.  This will be referred to 

as the "controlled environment".  Under these conditions, a more 


severe chromium deficiency resulted in very low glucose removal 

rates of 1.12%/min in 6 rats and of 0.18%/min in 4 female breeder 

rats (482 days old), after 11 days on a chromium-deficient diet.  

The removal rate in 4 control rats receiving the same diet with a 

chromium supplement improved from 0.51 to 1.39% during the same 

period (Mertz et al., 1965b).  This strong impairment of glucose 

tolerance in rats kept in the "controlled environment" was 

reflected in their fasting blood-glucose levels, compared with 

those of chromium-supplemented controls: 1370 ± 68 versus 1170 ± 17 

mg/litre in males and 1390 ± 68 versus 960 ± 65 mg/litre in 

females.  More than half of 185 deficient rats excreted more than 

0.25% glucose in the urine, whereas glycosuria was found in only 9 

of the chromium-supplemented controls (Schroeder, 1966).  A 

significant reduction in the intravenous glucose removal rate was 

also observed in 8 rats in plastic cages, fed an EDTA-washed low-

protein diet (7% casein), compared with 8 controls receiving 50 µg 

chromium as the chloride, by stomach tube, daily for 2 weeks (2.1 

versus 3.6%/min;  P < 0.01). However, chromium supplements did not 

improve the near-normal removal rates in rats receiving a 20% 

casein diet (Mickail et al., 1976).  Significantly lower plasma-

glucose levels, due to supplementation with chromium, were reported 

in rats fed the chromium-deficient Torula yeast diet (Whanger & 

Weswig, 1975).  In another series of studies, only a slight 

reduction in blood-glucose (from 1240 to 1180 µg/litre) was found 

in 10 rats receiving a diet supplemented with chromium (10 µg/kg) 

(Djahanshiri, 1976). 


    Impaired glucose tolerance in squirrel monkeys, fed a 

commercial laboratory chow, was shown to respond to chromium 

supplementation.  Of 9 monkeys with an impaired glucose removal 

rate (1.38%/min), 8 responded after 22 weeks of supplementation of 

their drinking-water (chromium acetate, 10 mg/litre) with a 

normalization of their glucose tolerance (average removal rate, N = 

9, 2.33 ± 0.3%/min) (Davidson & Blackwell, 1968).  There was no 

effect on food consumption, growth rate, or serum-insulin 

concentrations.  The chromium content of the commercial chow was 

stated to be 3.3 mg/kg, a very high concentration.  In view of the 

uncertainties of methods of analysis for chromium (section 2.2), it 

is not possible to interpret the results as indicative of a very 

high chromium requirement of the squirrel monkey or of an unusually 

poor bioavailability of the chromium in that particular ration.  A 

marginal chromium deficiency may have existed in mice fed a bread 

and milk diet, as daily administration of 10 µg chromium for 16 

days to 8 months produced a 10 - 30% decline in blood-glucose 

levels (Vakhrusheva, 1960).  However, this effect was not specific 

for chromium, as it was also observed when manganese was 



    The glucose tolerance of guinea-pigs did not differ 

significantly between groups fed diets containing chromium at 

0.125, 0.625, or 50 mg/kg, even though the animals fed the 2 higher 

levels exhibited a lower mortality rate during pregnancy (Preston 

et al., 1976). 


    Although the administration of synthetic glucose tolerance 

factor (a chromium-dinicotinic acid-glutathione complex) to 6 pigs 

did not affect glucose tolerance tests, it resulted in a 

significant increase in the hypoglycaemic effect of insulin 

injected at 0.1 U/kg body weight (Steele et al., 1977a). 


    Turkey poults, fed a practical ration containing chromium 

levels of 5 mg/kg, responded to chromium supplementation (20 mg/kg 

diet) with a significant increase in liver glycogen and in glycogen 

formation, following a fast, and with a significant increase in 

glycogen synthetase (EC activity in the liver (Rosebrough 

& Steele, 1981). 


    It can be concluded that the impairment of glucose tolerance in 

rats fed a low-chromium Torula yeast diet is due to chromium 

deficiency.  The effects of chromium in squirrel monkeys, pigs, and 

turkeys, though statistically significant, are somewhat difficult 

to interpret, because of the reported high chromium content of the 

basal diet.  No evidence for chromium deficiency has yet been 

obtained through glucose tolerance tests on other animal species. 


7.1.2.  Effects of deficiency on lipid metabolism


    Though trivalent chromium in high doses (2.5 mg/kg body weight) 

has been shown to increase the synthesis of fatty acids and 

cholesterol in the liver (Curran, 1954), lower, physiological doses 

appear to decrease serum-cholesterol concentrations in rats.  

Schroeder & Balassa (1965) found an average level of 927 mg 

cholesterol/litre serum in 24- to 26-month-old male rats, kept in a 

controlled environment and administered chromium in the drinking-

water at a concentration of 5 mg/litre, compared with an average of 

1229 mg/litre in controls not receiving chromium ( P < 0.01).  The 

effects in female rats were ambigous, one study producing the 

expected reduction in cholesterol due to chromium, another showing 

an elevation in the supplemented female rats.  Schroeder's 

observations of a cholesterol-reducing effect of chromium in male 

rats were confirmed by Staub et al. (1969) and by Whanger & Weswig 

(1975) but were contradicted by results of a third study in which 

there were not any significant effects of chromium on sucrose-

induced triglyceridaemia and cholesterolaemia (Bruckdorfer et al., 

1971).  Perhaps more significant than the effect on circulating 

cholesterol is the direct effect of chromium on the occurrence of 

aortic plaques. Schroeder & Balassa (1965) observed 6 plaques in 54 

male and female chromium-deficient rats, but only one plaque in 48 

animals receiving 5 mg chromium/litre in drinking-water. These 

results are in agreement with those from a subsequent report of the 

protective effect of the natural chromium content of water (60 - 

215 µg/litre) against atherosclerosis in cholesterol-fed rabbits 

(Novakova et al., 1974).  Abraham et al. (1980) extended these 

observations by demonstrating that daily chromium injections (20 µg 

K2CrO4) reversed the established atherosclerosis in the aorta of 11 

cholesterol-fed rabbits, compared with 12 controls.  The mean 

plaque area was reduced from 95% to 63%, the total aortic 

cholesterol from 729 mg to 458 mg, and the atheromatous lesions, as 


measured by technetium incorporation from 285 000 cpm to 114 000 

cpm, all differences being statistically significant.  These 

results are reinforced by observations in man discussed in section 



7.1.3.  Effects of deficiency on life span, growth, and 



    The mortality of male, but not of female mice, raised in a 

"controlled environment" (section 7.1.1) was reduced by trivalent 

chromium administered as acetate in the drinking-water at a 

concentration of 5 mg/litre (Schroeder et al., 1964).  The survival 

rates at 12 months were 92.6% and 68.8% ( P < 0.0001) in 

supplemented and deficient animals, respectively.  Similary, male, 

but not female, rats receiving a chromium concentration of 5 

mg/litre in the drinking-water had longer life spans than deficient 

controls.  The mean age of the last surviving 10% of animals was 

1249 days, compared with 1141 days in the deficient animals ( P < 

0.01). Survival of male rats fed a low-chromium (< 100 µg/kg), 

low-protein ration and subjected to a controlled acute haemorrhage 

was significantly less than that of chromium-supplemented rats, in 

2 studies (67 versus 92%;  P < 0.05 and 27 versus 60%;  P < 0.01, 

respectively) (Mertz & Roginski, 1969). 


    In Schroeder's study, growth rates in treated mice and rats of 

both sexes raised in a "controlled environment", were higher after 

6 and 12 months, with highly significant differences in body weight 

ranging from 9 to 17% ( P < 0.005) compared with the controls.  

Again, the effects of chromium supplementation were greater in 

males than in females (Schroeder et al., 1964, 1965). 


    Similar results were reported by Djahanschiri (1976), who 

studied a total of 2750 rats of a special inbred strain (Hk51) fed 

a basal diet (0.15 mg chromium/kg diet) and chromium supplements 

ranging from 10 to 500 mg/kg diet.  At 12 weeks, the average 

weights of the chromium-supplemented animals, regardless of dose 

level, were significantly higher (by 6% in the males and 3% in the 

females) than those of the animals on the basal diet.  The same 

author reported a progressive diminution in both the milk 

production of lactating rats and weight gain in 3 consecutive 

generations fed the low-chromium diet, compared with rats receiving 

chromium supplementation. Increased mortality was reported in 

pregnant guinea-pigs fed a low-chromium diet (125 µg/kg diet) 

compared with animals receiving a chromium supplement of either 625 

µg/kg or 50 mg/kg (Preston et al., 1976). 


    When rats raised on a low-chromium Torula yeast diet (< 100 

g/kg) mated with those on a normal diet, they were able to 

impregnate the females at a 100% conception rate only up to the age 

of 4 months.  After this age, the conception rate declined to 25%, 

25%, and 0%, at the age of 7, 8, and 9 months, respectively.  This 

decline was accompanied by a significant ( P < 0.01) decrease in 

the sperm count in the chromium-deficient males to approximately 

half of the count in supplemented controls at the age of 8 months 

(Anderson & Polansky, 1981). 


7.1.4.  Other effects of deficiency


    Male weanling rats, fed a 10% soya protein ration with a 

chromium content of less than 100 µg/kg, developed a visible 

opacity of the cornea in one or both eyes. In several studies, the 

incidence of this effect ranged from 10 to 15% in deficient rats.  

No opacities developed in control animals receiving 2 mg 

chromium/kg diet (Roginski & Mertz, 1967). 


    Chromium deficiency has been shown to reduce the physical 

performance of rats under stress.  Ten male rats raised on a 

chromium-deficient diet (150 µg/kg diet) swam for an average of 250 

min, until exhaustion, in contrast with 10 rats receiving a 

supplement of 10 mg chromium/kg diet, which were exhausted only 

after 320 min (Djahanschiri, 1976). 


7.1.5.  Mechanism of action of chromium as an essential nutrient  Enzymes, nucleic acids, and thyroid


    Chromium is present in nucleic acids in very high 

concentrations, but the function of these is not clear at present 

(Mertz, 1969).  However, recent work suggests a biological function 

of chromium in nucleic acid metabolism (Okada et al., 1984).  

Ribonucleic acid synthesis in mouse liver was significantly 

increased by as little as 1 µmol trivalent chromium, in the 

presence of DNA or chromatin (Okada et al., 1981).  These effects 

were also present when the DNA or chromatin were first complexed 

with chromium prior to incubation.  However, prior complexation of 

RNA polymerase with chromium depressed activity.  These effects 

were obtained  in vitro with a concentration (52 µg/litre) that is 

similar to physiological levels.  Goncharov (1968) presented data 

suggesting that chromium is involved in the function of the thyroid 

gland.  These findings have been supported by Lifschitz et al. 



    An oligopeptide with a relative molecular mass of 1480, which 

was crystallized from liver tissue, had a specific affinity for 

chromium (Wu, 1981).  Interaction of chromium with insulin


    The interaction of chromium with insulin has been extensively 

studied and can therefore be presented in some detail, but this 

does not imply that this is the only, or the most important, 

function of chromium. 


    The effects of chromium  in vitro, and probably in vivo, depend 

on the presence of endogenous or exogenous insulin, no effects 

having been demonstrated in  in vitro systems that did not either 

depend on, or contain, insulin. Chromium deficiency causes an 

impaired response to added insulin in rat epididymal fat tissue, 

and, when glucose uptake or glucose oxidation or utilization for 

lipid synthesis is measured, the dose-effect curve is flat.  

Addition of suitable chromium compounds significantly increases the 


slope of the curve (Fig. 3).  This demonstrates the true 

potentiation of the insulin action and indicates that chromium 

alone does not act as an insulin-like substance (Mertz et al., 

1961; Mertz & Roginski, 1971; Mertz, 1981).  Chromium was also 

shown to stimulate the transport of D-galactose into epididymal fat 

cells.  This suggests cell transport, the first step of sugar 

metabolism, as a major site of action for chromium (Mertz & 

Roginski, 1963).  Insulin-potentiating effects have also been 

observed on the swelling of liver mitochondria (Campbell & Mertz, 

1963) and on glucose utilization in isolated rat lens (Farkas & 

Roberson, 1965). 




    Stimulation of the effects of insulin has been observed in a 

glucose-independent, but insulin-responsive, system.  Significantly 

more alpha-amino isobutyric acid (a non-metabolizable amino acid 

analogue) was incorporated into the heart and liver tissue of 

chromium-supplemented male rats than in the tissues of chromium-

deficient controls, in response to the  in vivo injection of the 

labelled analogue and insulin (Roginski & Mertz, 1969). 


    These observations suggest a peripheral action of chromium to 

facilitate the action of insulin; no evidence has been produced 

indicating that chromium plays any role in the production, storage, 

or release of insulin by the pancreas. Thus, the primary result of 

chromium deficiency is a diminution in the effectiveness of 

insulin.  The resulting metabolic impairment may be compensated for 

by increased insulin production in some cases, resulting in 

elevated concentrations of the hormone, but not enough data exist 


from experimental animal studies to assess the action of the 

element on insulin metabolism.  More information is available for 

human subjects and this is discussed in section 8.1.  The 

interaction between chromium, insulin, and receptor sites of liver 

mitochondrial membranes was studied using polarographic techniques.  

The results formed the basis for the hypothesis that chromium may 

facilitate bond formation between the intra-chain disulfide of 

insulin and sulfur-containing groups of the receptors, by 

participating in a ternary complex (Christian et al., 1963). 


    This hypothesis is consistent with results of studies on rats 

fed, either a low-chromium Torula yeast diet or a brewer's yeast 

diet known to be adequate in chromium.  While the insulin-binding 

capacity of hepatocytes was not significantly different, the 

insulin affinity of the cells was significantly greater ( P < 0.01) 

for the chromium-adequate rats than for the deficient Torula yeast 

rats (Steele et al., 1977b). 


7.1.6.  Chromium nutritional requirements of animals


    In the preceding sections, studies were evaluated in which the 

effects of chromium supplementation were determined in animals that 

were at least marginally chromium deficient.  In other studies, the 

effects of chromium were investigated in animal systems in which 

the existence of chromium deficiency was either not ascertained or 

not investigated.  Before these studies are described and 

interpreted for the determination of chromium nutritional 

requirements of animals, it is helpful to consider them against the 

background of Venchikov's (1974) model.  This model is generally 

applicable to trace element effects defining 3 zones of action, the 

zone of biological action, that of pharmacodynamic action, and that 

of toxicity (Fig. 4).  The biological zone, in response to 

supplements with low amounts of an element, represents the 

correction of a deficiency and the resulting level of biological 

activity is that of optimal function.  Increasing the amount of 

supplement further may lead to a certain depression, followed by a 

zone of new, increased activity, in which the element no longer 

acts as an essential nutrient, but as a drug.  Still greater 

supplements, beyond the homeostatic control capability of the 

organism produce toxic effects and death.  Because all the studies 

described subsequently involved amounts of chromium supplements 

that were higher than the levels normally needed to correct a 

deficiency, it is possible, according to Venchikov's definition, 

that the observed effects might be pharmacological. 




    Tuman & Doisy (1977) studied the effects of yeast concentrates 

of high chromium (glucose tolerance factor) content and of 

synthetic chromium complexes with GTF activity (Tuman et al., 1978) 

in mice, raised on a presumably complete commercial stock diet.  

Six animals were used for each test, either genetically diabetic 

mice or their control litter mates of the C57Bl-KSI strain.  

Injections of either 5 mg of the GTF-containing yeast extracts or 

0.1 mg of the synthetic chromium complex, acutely reduced the 

elevated plasma-glucose levels in the diabetic and the non-fasting 

normal mice by 10 - 38% of the initial values ( P < 0.01) and the 

plasma-triglycerides by 26 - 56% ( P < 0.01), compared with control 

mice injected with saline.  Injection of insulin into diabetic mice 

produced only an 11 - 18% decrease in plasma-glucose levels, 

whereas injection of the GTF-containing extract together with 

insulin reduced plasma-glucose levels by 39 - 51% and plasma-

triglyceride levels by 76% (Table 11). 


    The results suggest either a much higher increase in the 

chromium requirement of the genetically diabetic mice or their 

inability to use chromium in the diet. 


Table 11.  Acute effects of GTF and exogenous insulin on non-

fasting plasma-glucose and plasma-triglyceride (TG) concentrations 

in 19-week-old genetically diabetic micea


Treatment  Plasma-   deltaGlucose   Plasma- deltaTG

           glucoseb                    triglyceridesb

           (mg/litre)                  (mg/litre)


saline     11 120 ±                 3960 ± 160(5)c



GTF        9320 ±   -180 (16%)   2790 ± 170(5)d -117 (30%)



insulin    9840 ±   -128 (12%)   3020 ± 400(5) - 94 (24%)



insulin    7060 ±   -406 (37%)   940 ± 220(5)e -302 (76%)

and GTF    840(5)e


a   Modified from: Tuman & Doisy (1977).

b   Glucose and triglyceride values represent mean ± SEM for 6 mice in

    each treatment group. Dose of GTF was 5 mg (WL-10-AT) administered

    intraperitoneally, 12 h prior to collection of blood. Lente insulin

    (0.1 U per mouse) was administered subcutaneously, 12 h prior to

    collection of blood. Data were treated by analysis of variance to

    detect differences between the various treatment groups; independent

    orthogonal comparisons were performed in the following groups ( P value

    indicates level of significance for each comparison).

c   Saline versus all other treatments,  P < 0.005.

d   GTF versus insulin,  P < 0.05.

e   GTF and insulin alone versus combined GTF and insulin,  P < 0.005.

    Thus, GTF and insulin > GTF = insulin > saline.


    Steele & Rosebrough (1979) reported a significant stimulation 

of the growth rate of one-week-old turkey poults (both sexes) by 

supplementation of a practical ration with 20 mg chromium (as 

chloride)/kg.  The weight gains within the 2-week study were 235 g 

and 267 g for the 60 controls and 60 supplemented turkeys, 

respectively ( P < 0.001).  As the practical ration contained 

ground yellow corn and soybean meal, limestone, and dicalcium 

phosphate, chromium deficiency would appear unlikely.  The amount 

of the chromium supplement (20 mg/kg diet) is quite high, and 

further studies are needed to decide whether the observed effects 

were of a pharmaco-dynamic nature or truly nutritional, i.e., 

correcting a deficiency.  A similar interpretation should be 

applied to a report of improved egg quality in the laying hen 

(Jensen et al., 1978). 


    The quantitative aspects of the effects of chromium on animals 

can be summarized as follows: normal rats fed semi-purified, semi-

synthetic rations, with Torula yeast or individual proteins and 

sucrose or starch as the source of carbohydrates, develop mild 

signs of deficiency at a dietary level of 100 - 150 µg chromium/kg.  

To prevent deficiency, most authors used very high supplements of 

several mg/kg diet and did not determine the biological 

availability of the chromium complexes used for the 

supplementation.  Diets containing raw ingredients and supplying 

chromium levels between 0.5 and 1 mg/kg do not induce signs of 

deficiency and probably meet the requirement of the rat.  A very 

tentative estimate of the dietary chromium need of the rat and 

probably the mouse would be approximately 0.5 mg/kg diet.  This 

estimate should be interpreted with caution, because of the lack of 

knowledge concerning the biological availability of chromium and of 

its interaction with dietary constituents. 


7.2.  Toxicity Studies


    The toxicology of chromium compounds has been reviewed by the 

US National Academy of Science (US NAS, 1974a), Langard & Norseth 

(1979), the International Agency for Research on Cancer (IARC, 

1980), Langard (1980a, 1982), and Burrows (1983). 


    In discussing toxicological problems, it is important to 

differentiate between the various oxidation states of chromium and 

its compounds.  Trivalent chromium, when administered to animals in 

food or water, does not appear to induce any harmful effects, even 

when given in large doses (US NAS, 1974a) (section 7.2.1).  Acute 

and chronic toxic effects of chromium are mainly caused by 

hexavalent compounds.  Since it has been shown that both industrial 

trivalent chromium compounds as well as reagent-grade trivalent 

chromium compounds can be contaminated by hexavalent chromium 

(Petrilli & DeFlora, 1978a; Levis & Majone, 1979), the evaluation 

of experimental studies becomes difficult, especially when the 

purity of the chemical compounds used is not known. 


    Discrimination between the biological effects, caused by 

hexavalent chromium and trivalent chromium is difficult, because, 

after penetration of membranes in tissues, hexavalent chromium is 

immediately reduced to trivalent chromium (Gray & Sterling, 1950; 


US NAS, 1974a), and it is not evident whether the observed 

phenomena are caused by this reduction or even by the trapping of 

trivalent chromium by ligands after uptake in the cells.  Another 

problem in evaluating the data is associated with the route of 

administration.  Hexavalent chromium, introduced by the oral route, 

is partly reduced to trivalent chromium by acidic gastric juice 

(Donaldson & Barreras, 1966; DeFlora & Boido, 1980); thus, the 

effects or lack of effects observed may be caused mainly by 

trivalent chromium and not by the hexavalent chromium, actually 



7.2.1.  Effects on experimental animals


    Many local effects on human beings have been reported (section 

8.3), but only a few studies have verified these effects in 

experimental animals.  A comprehensive survey of hexavalent 

chromium-induced effects is given in Table 12 (US NAS, 1974a).  For 

most studies, details were not given of the length of exposure, 

number of treated animals and controls, etc.  Diagnoses were stated 

without presenting all the original data.  Thus, in this section, 

some papers will be discussed that refer to the most prominent 

local and systemic effects to support and clarify the effects shown 

in human beings. 


    It is evident that the toxicity of hexavalent chromium in 

animals varies with the route of entry into the body.  Low 

concentrations of hexavalent chromium may be tolerated, when 

administered in the feed or drinking-water, the extent of 

absorption being a factor of importance.  For example, rats 

tolerated hexavalent chromium in drinking-water at 25 mg/litre, for 

1 year, and dogs did not show any effects from chromium 

administered as potassium chromate at 0.45 - 11.2 mg/litre over a 

4-year period (US NAS, 1974a).  However, oral exposure of both male 

and female rabbits to sodium dichromate (0.1% solution, 0.2 - 5 

mg/kg body weight, for up to 545 days) resulted in significant 

morphological changes in the gonads, including atrophy of the 

epithelium and dystrophic alterations of the Sertoli and Leydig 

cells in the testes, and sclerotic and atrophic changes in ovaries 

(Kucher, 1966). 


    Larger doses of hexavalent chromium are highly toxic and may 

cause death, especially when injected iv, subcutaneously (sc), or 

intragastrically.  The LD50 of chromium compounds was determined 

for several experimental animal species.  The LD50 of potassium 

dichromate (hexavalent chromium), administered orally (stomach 

tube) to rats, was 177 mg/kg body weight in males and 149 mg/kg 

body weight in females (Hertel, 1982). When injected iv in mice 

(sex not given), the LD50 of chromium carbonyl was 30 mg/kg body 

weight (IARC, 1980). 


    Performing a life-time inhalation study on the rat, Glaser et 

  1. (1984) found an LC50 for Na2Cr2O7 of 28.1 mg/m3 (range, 16.7 - 

47.3 mg/m3).  Assuming a deposition rate in the lung of 30% of the 

dose administered, the LC50 dose was 1 mg/kg body weight in male 

and 1.2 mg/kg in female rats. 

Table 12.  Effects of hexavalent chromium in animalsa


Animal    Route   Compound(s)     Average dose   Duration Effect            Reference

                                      or concentration


Rabbit,   inhalation  chromates     1 - 50 mg/m3   14 h/day for pathological      Lukanin (1930)

cat                                                     1 - 8 months changes     

                                                                       in the lungs


Rabbit    inhalation  dichromates     11 - 23 mg/m3   2 - 3 h/day none              Lehmann (1914)

                      as dichromate                     for 5 days


Cat       inhalation  dichromates     11 - 23 mg/m3   2 - 3 h/day bronchitis,       Lehmann (1914)

                      as dichromate                     for 5 days pneumonia           

                                                                       perforation of

                                                                       nasal septum  


Mouse     inhalation  mixed dust     1.5 mg/m3   4 h/day, no tumours        Baetjer et al.

                      containing      as CrO3   5 days/week,               (1959a);

                      chromates                         for 1 year Steffee &

                                                                                         Baetjer (1965)


Mouse     inhalation  mixed dust     16 - 27 mg/m3   1/2 h/day tumours in        Baetjer et al.

                      containing      as CrO3   intermit- some strains      (1959a);

                      chromates                         tently Steffee &

                                                                                         Baetjer (1965)


Mouse     inhalation  mixed dust     7 mg/m3   37 h over increased         Baetjer et al.

                      containing      as CrO3   10 days tumour rate       (1959a);

                      chromates                                                          Steffee &

                                                                                         Baetjer (1965)


Rat       inhalation  mixed dust     7 mg/m3   37 h over barely            Baetjer et al.

                      containing      as CrO3   10 days toleratedb        (1959a);

                      chromates                                                          Steffee &

                                                                                         Baetjer (1965)


Rabbit,   inhalation  mixed dust     5 mg/m3   4 h/day, none marked       Baetjer et al.

guinea-               containing as CrO3           5 days/week, (1959a);

pig                   chromates             for 1 year Steffee &

                                                                                         Baetjer (1965)



Table 12.  (contd.)


Animal    Route   Compound(s)     Average dose   Duration Effect            Reference

                                      or concentration


Rat,      inhalation  hexacarbonyl    1.6 mg/m3   4 months, anaemia; lipid    Roschina (1976)

rabbit                                                  4 h, 5 days and/or protein      

                                                        a week         dystrophia  

                                                                       in liver          

                                                                       and kidneys       


Rat,      inhalation  hexacarbonyl    0.16 mg/m3   4 months, anaemia; no       Roschina (1976)

rabbit                                                  4 h, 5 days biochemical             

                                                        a week         or morphological



Rat       inhalation  hexacarbonyl    35 mg/m3   30 min 100% death        Roschina (1976)


Rat       inhalation  dichromates     0.006 - 0.2   28 days/ increase in       Glaser et al.

                                      mg/m3             90 days lung-macrophages  (1985)

                                                        23 h/day                  

                                                        7 days/week    lymphocytes


                                                                       reduced Fe2O3

                                                                       lung clearance


Rat       intratra-   dichromates     5 per week   up to 30 toleratedc        Steinhoff

          cheal in-                   0.01 - 0.25 months                       et al. (1983)

          stillation                  mg/kg


Rat       intratra-   dichromates     1 per week   up to 30 tolerated;        Steinhoff

          cheal in-                   0.05 - 1.25 months     1.25 mg/kg et al. (1983)

          stillation                  mg/kg     harmful


Rat       oral   potassium     500 mg/litre   daily maximal           Gross & Heller

                      chromate in                                      non-toxic (1946)

                      drinking-water                                   concentration


Rat,      oral   zinc chromate   10 g/kg   daily maximal           Gross & Heller

mouse                 in feed                           non-toxic (1946)

(mature)                                                               concentration



Table 12.  (contd.)


Animal    Route   Compound(s)     Average dose   Duration Effect            Reference

                                      or concentration



Rabbit    oral   sodium di-     0.2 - 5.0 mg/kg   545 days morphological     Kucher (1966)

                      chromate                                         changes in               

                                                                       gonads (testes:          

                                                                       atrophy of               



                                                                       alterations of           

                                                                       Sertoli &                

                                                                       Leydiz alls.             


                                                                       sclerotic and            




Rat       oral   zinc chromate   1.2 g/kg   daily maximal           Gross & Heller

(young)               in feed                           non-toxic (1946)



Rat       oral   potassium     1.2 g/kg   daily maximal           Gross & Heller

(young)               chromate                           non-toxic (1946)

                      in feed                                          concentration


Dog,      oral   monochromate    1.9 - 5.5 mg   29 - 685 none harmful      Lehmann (1914)

cat,                  or dichromates chromium/kg       days

rabbit                                body weight per

                                      day 1 mg chrom-

                                      ium equivalent

                                      to 2.83 mg


                                      or 3.8 mg




Table 12.  (contd.)


Animal    Route   Compound(s)     Average dose   Duration Effect            Reference

                                      or concentration


Dog       oral   potassium     1 - 2 g as   daily fatal in 3        Brard (1935)

                      dichromate      chromium                 months anaemia


Dog       stomach   potassium     1 - 10 g as   - rapidly fatald    Brard (1935)

          tube        dichromate     chromium


Monkey    subcutan-   potassium     0.02 - 0.7 g in   - fatald            Hunter & Roberts

          eous        dichromate     2% solution                                   (1933)


Dog       subcutan-   potassium     210 mg as   - rapidly fatal     Brard (1935)

          eous        dichromate     chromium


Guinea-   subcutan-   potassium     10 mg   - lethald           Ophüls (1911a)

pig       eous   dichromate                                                       Ophüls (1911b)


Rabbit    subcutan-   potassium     1.5 cc of 1%   - 80% fatald        Hasegawa (1938)

          eous        dichromate     solution/kg body



Rabbit    subcutan-   potassium     20 mg   - lethald           Ohta (1940)

          eous        dichromate


Rabbit    subcutan-   potassium     0.5 - 1 cc of   - nephritisd        Ohta (1940)

          eous        dichromate     0.5% solution/kg

                                      body weight


Rabbit,   subcutan-   sodium     0.1 - 0.3 g as   - rapid deathd      Priestley

guinea-   eous or   chromate     CrO3                 fall in blood (1877)

pig       intravenous                                                  pressure


Rabbit    intra-   potassium     0.7 cc of 2%   - lethald           Mazgon (1932)

          venous                      solution/kg     8-10 days after

                                      body weight                      injection


Dog       intra-   potassium     10 grains   - instant death     Gmelin (1826)

          venous      chromate



Table 12.  (contd.)


Animal    Route   Compound(s)     Average dose   Duration Effect            Reference

                                      or concentration



Dog       intra-   potassium     1 grain   - none marked       Gmelin (1826)

          venous      chromate


Dog       intra-   potassium     210 mg as   - rapidly fatal     Brard (1935)

          venous      dichromate     chromium


Dog       intra-   potassium     3 mg/100 cc   2 doses marked renal      Hepler & Simonds

          venous      dichromate     blood per dose                 damage (1946); Simonds

                                                                                         & Hepler (1945)


a  Modifed from: US NAS (1974a).

b  Pathological changes in experimental and control rats, 101 weeks after exposure.

c  The same weekly dose distributed over 5 days was clearly better tolerated than a single weekly 


d  Renal damage.

    A local corrosive action of hexavalent chromium on the skin, 

similar to that seen in man, was described by Samitz & Epstein 

(1962), who induced chrome ulcers in guinea-pigs at 4 trauma sites, 

with daily exposure to 0.34 MK2Cr2O7 solution for 3 days.  Mosinger 

& Fiorentini (1954) showed the same effects using potassium 



    Following parenteral administration, the most common systemic 

effects of chromium were parenchymatous changes in the liver and 

kidney (Mosinger & Fiorentini, 1954).  Later studies showed 

selective damage in the renal proximal convoluted tubules, without 

evidence of glomerular damage, as demonstrated after one single sc 

injection of potassium dichromate of 10 mg/kg body weight (Schubert 

et al., 1970) or after one single intraperitoneal (ip) injection of 

sodium chromate of 10 or 20 mg/kg body weight (Evan & Dail, 1974). 

Effects have also been found in fish (Strik et al., 1975). After 32 

days of continuous exposure to 0.1, 1, or 10 mg hexavalent chromium 

(as potassium dichromate)/litre, the fish  Rutilus rutilus developed 

lysis of the intestinal epithelium with haemorrhages as well as 

hypertrophy and hyperplasia of the gill epithelium. 


    Franchini et al. (1978) found an increase in urinary protein, 

lysozyme, glucose, and beta-glucuronidase in rats after a single sc 

injection of potassium dichromate at 15 mg/kg body weight.  After 

sc injection (3 mg/kg body weight), every other day for 2 - 8 

weeks, the authors observed a correlation between the chromium 

contents of the renal cortex and chromium clearance. 


    Five-week-old male Wistar rats of the strain TNO-W-74 were 

continuously exposed in inhalation chambers to submicron aerosols 

of sodium dichromate at concentrations ranging from 25 (low level) 

to 200 µg chromium/m3 (high level) (Glaser et al., 1985).  Exposure 

for 28 days to 25 or 50 µg chromium/m3 resulted in "activated" 

alveolar macrophages with stimulated phagocytic activity, and 

significantly elevated antibody responses to injected sheep red 

blood cells.  After 90 days of low-level exposure, there was a more 

pronounced effect on the activation of the alveolar macrophages, 

with increased phagocytic activity. However, inhibited phagocytic 

function of the alveolar macrophages was seen at the high 

hexavalent chromium exposure level (200 µg/m3).  In rats exposed to 

this chromium aerosol concentration for 42 days, the lung clearance 

of inert iron oxide was significantly reduced.  The humoral immune 

system was still stimulated at a low chromium aerosol concentration 

of 100 µg/m3, but significantly depressed at 200 µg chromium/m3. 


    Exposure of rats, through inhalation, to chromium carbide or 

chromium boride dust at very high levels (300 - 350 mg/m3 for each 

substance) for 3 months (2 h/day) resulted in effects on the 

vascular system of the lungs, e.g., endothelial hyperplasia.  

Bronchitis and a decrease in the blood-haemoglobin concentration 

were also observed (Roschina, 1964). The effects of chromium boride 

were more pronounced than those of chromium carbide. 


    Steinhoff et al. (1983) performed an intracheal injection study 

on rats (930 rats, 30 months, 0.05 - 1.25 mg Na2Cr2O7/kg body 

weight per week; 1.25 mg CaCrO4/kg body weight per week).  Half of 

the rats were intratracheally injected once a week and the other 

half received the same weekly dose distributed over 5 injections 

per week.  In rats receiving doses 5 times a week, there were some 

significant changes in levels of total plasma-protein and 

-cholesterol, in some haematological variables, in organ weights, 

and in survival times in females.  Only male rats receiving 1.25 mg 


sodium dichromate/kg body weight, once a week, showed a sharp 

reduction in body weight, female rats being less affected. Rats 

receiving calcium chromate in the same dose showed reduced body 

weight but to a lesser extent.  The weight of lung and trachea was 

increased by both substances in all doses. 


    Marked histopathological changes (congestion, fairly large 

areas of focal necrosis, bile duct proliferation) described after 

long-term exposure of rabbits to hexavalent chromium (ip injection 

of 2 mg chromium/kg body weight per day for 6 weeks) (Tandon et 

al., 1978), as well as the increase in hepatic metallothionein and 

decrease in cytochrome P-450 levels after ip injection of 400 µmol 

chromium/kg per day (type of chromium compound not mentioned) 

(Eaton et al., 1980) need further confirmation.  The finding of an 

accumulation of hexavalent chromium in the reticuloendothelial 

system including bone marrow (Baetjer et al., 1959b; Langard, 1977) 

may be of importance for a disturbed blood picture. 


    Merkurieva et al. (1980a,b) studied the effects of potassium 

dichromate in the drinking-water on the activities of different 

enzymes in rats.  Exposure included daily doses of 0.0005, 0.005, 

0.05, or 0.5 mg/kg body weight for up to 6 months.  After 20 days 

of exposure at the highest dose level, enzyme activities increased 

by 15 - 28% in liver microsomes (inosine-5-diphosphatase), 

lysosomes (beta-D-galactosidase), and cytosol (lactate dehydrogenase 

(EC  For some of these enzymes, as well as for 

acetylesterase (EC, increases in activity of up to 54% 

were found in the gonads, kidneys, seminal fluid, and serum.  At a 

dose of 0.05 mg/kg, the only statistically significant finding was 

a 54% increase in the activity of acetylesterase in the gonads.  

After a 6-month exposure at this dose level, there was a 70% 

increase in lactate dehydrogenase activity in the seminal fluid as 

well as a 50% increase in free beta-galactosidase in the liver.  There 

were no changes in enzyme activities at the two lowest dose levels. 


    Painting of rat skin with an aqueous solution of potassium 

dichromate (0.5%), daily, for 20 days, resulted in a local 

inflammatory reaction, an increased level of hexose glyco-proteins 

in the skin and serum, and an elevated concentration of serotonin 

in the skin and liver (Merkurieva et al., 1982). Most of these 

effects were also seen earlier in the exposure period, though they 

were not as pronounced.  Ten days after the start of exposure, a 

nearly 3-fold increase in the serum-acetylcholine concentration 

occurred together with decreased acetylcholinesterase activity.  

Thus, the data of Merkurieva et al. show systemic effects following 

both oral and dermal exposure to hexavalent chromium. 


    Cats fed chromic phosphate or oxydicarbonate at 50 - 1000 mg/day 

for 80 days did not exhibit signs of illness or tissue damage.  

Similarly, toxic reactions were not observed in rats administered 

drinking-water containing 25 mg trivalent chromium/litre, for 1 

year, or 5 mg trivalent chromium/litre throughout their lifetime 

(US NAS, 1974a).  The toxicity of trivalent chromium is so low that 

even by parenteral administration, a chromic acetate level of 2.29 

g/kg body weight or a chromic chloride level of 0.8 g/kg body 


weight is required to kill mice.  Even very large doses given 

intragastrically were not fatal for dogs.  Brard (1935) reported 

that 10 or 15 g of chromium as chromic chloride proved fatal in one 

dog (US NAS, 1974a).  Some fatal doses of trivalent chromium 

compounds reported in the literature are listed in Table 13. 


    Rats exposed through inhalation to chromic oxide (trivalent 

chromium) at 42 mg/m3 or to chromic phosphate at 43 mg/m3 (5 h/day 

for 5 days/week) for 4 months developed chronic irritation of the 

bronchus and lung parenchyma, and dystrophic changes in the liver 

and kidney (Blokin & Trop, 1977). 


    Inhalation exposure of rats (number not given) to dusts 

containing 36 or 50% chromite for 4 months (2 h/day), at 

concentrations of 375 - 400 mg/m3, resulted in thickening of the 

walls of pulmonary vessels and bronchi (Roschina, 1959). The high 

exposure levels in these studies make it difficult to evaluate the 



    Inhalation studies have also been performed with chromium 

carbonyl, where chromium is in the 0 oxidation state (Roschina, 

1976).  Twelve rabbits and 48 rats were exposed for 4 months (4 

h/day, 6 days/week) at a concentration of 1.6 or 0.16 mg/m3.  At 

both exposure levels, there was loss of body weight (25 and 12%, 

respectively) as well as anaemia and leukocytosis.  In the higher 

exposure group, the animals showed an elevated gamma-globulin level 

in serum and an increased transaminase activity.  The contents of 

cholesterol and SH-groups were reduced, and there was a decrease in 

cholinesterase (EC activity.  Lipid and/or protein 

dystrophy were noted in several organs, e.g., in the liver and 

kidneys.  No such effects were detected in the animals in the low-

exposure group. 

Table 13.  Fatal doses of trivalent chromium in animalsa


Animal  Number of  Routeb Compound             Chromium Effect Reference

        animals            dose (g/kg)


Dog     2   sc chromic chloride     0.8 fatal Brard (1935)

Rabbit  1   sc chromic chloride     0.52 fatal Brard (1935)

Rat     38   iv chrome alum          0.01 - 0.018 LD50 Mertz et al.

                           chromium-hexaurea                           (1965a)


Mouse   -c   iv chromic chloride     0.8 MLDd Windholz et al. (1960)

Mouse   -c   iv chromic acetate      2.29 MLD Windholz et al. (1960)

Mouse   -c   iv chromic chloride     0.4 MLD Schroeder (1970)

Mouse   -c   iv trivalent chromium ? 0.25 - 2.3     MLD Windholz et al. (1960)

Mouse   -c   iv chromic sulfate      0.247 MLD Windholz et al. (1976)

Mouse   -c   iv chromic sulfate      0.085 MLD Schroeder (1970)

Mouse   -c   iv chromium carbonyl    0.03 LD50 Schroeder (1970)


a Modified from: US NAS (1974a).

b sc = subcutaneous; iv = intravenous.

c No figures given.

d Minimum lethal dose.  Carcinogenicity


    Various types of chromium chemicals, methods of administration, 

and species of animals have been studied (IARC, 1980a). 


    Ideally, carcinogenicity should be tested with the methods 

recommended by IARC (1980b), but, in many of the early studies, 

this was not done.  Carcinomas of the lung have been reported in 

animals as a result of the administration of chromium chemicals.  

Hueper (1958) found 2 squamous cell carcinomas and one 

carcinosarcoma in 25 rats following intra-pleural injection of 

chromite ore roast.  After intrapleural implantation of strontium 

chromate lasting 27 months, Hueper (1961) found tumours (type 

unspecified) in 17/28 rats.  Laskin et al. (1970) and Levy & Venitt 

(1975) produced a number of bronchogenic carcinomas by implanting 

pellets of cholesterol mixed with various chromium compounds 

encased in a wire mesh cage in the bronchi of rats.  Calcium and 

zinc potassium chromate produced a number of bronchogenic 

carcinomas, but soluble chromates and trivalent chromium chemicals 

failed to produce cancer. 


    Using the same technique, Levy & Martin (1983) tested 21

different chromium-containing materials (pigments, intermediates, 

and residues from the bichromate-producing industry, relatively 

pure crystalline compounds) in 2250 random-bred rats and found that 

chromates, described as sparingly soluble, were carcinogenic in the 

rat lung.  These materials included strontium and calcium chromate 

and, to a far lesser extent, certain forms of zinc chromate.  

Barium and lead chromate evoked only a very weak carcinogenic 

response compared with strontium and calcium chromate.  In the 

study of Laskin et al. (1970), it was shown that chromium trioxide 

produced hepatocellular carcinomas in 2/100 rats (controls, 0/24). 


    After inhalation of 13 mg calcium chromate/m3 (5 h/day, 5

days/week, for lifetime), Nettesheim et al. (1971) found 14 lung 

adenomas in 136 treated mice and 5 in 136 untreated controls, but 

no carcinomas.  Steffee & Baetjer (1965), performing inhalation 

studies on rats, mice, guinea-pigs, and rabbits (inhalation of 

mixed chromate dust, corresponding to 3 - 4 mg CrO3/m3, 4 - 5 

h/day, 4 days/week, for lifetime, or 50 months, respectively) could 

only find 3 alveologenic adenomas in 50 treated guinea-pigs.  

Laskin (1972) and Laskin et al. (1970) found 1 squamous cell 

carcinoma of the lung, 1 of the larynx and 1 "peritruncal tumor" in 

rats (inhalation of calcium chromate, 2 mg/m3, 589 exposures of 5 h 

over 891 days) and 1 squamous cell carcinoma and 1 papilloma of the 

larynx in hamsters.  The number of treated animals was not 

specified in either paper.  Steinhoff et al. (1983) performed 

intratracheal instillations of chromates in rats for 30 months with 

one treatment/week and the same weekly dose distributed over 5 

treatments/week (Table 14).  In 880 exposed rats, 28 adenomas of 

alveolar-bronchiolar origin (benign) and 12 malignant tumours (3 

adenocarcinomas and 9 squamous cell carcinomas) were found.  All 

lung tumours developed very late and were only detected at the end 

of the lifetime study, often in lungs with callosities.  The 

tumours were tiny and none of them caused the animal to die.  


Sodium dichromate was not carcinogenic after exposure on 5 

days/week.  With calcium chromate, the carcinogenic effect was more 

pronounced after treatment once per week, than after treatment 5 

times per week. 


Table 14.  Incidence of benign and malignant lung tumours among 

880 rats intracheally injected with Na dichromate and Ca chromatea

INTOX Home Page






    Hyperglycaemia is defined as a blood glucose concentration greater

    than 115 mg/dL (6.3 mmol/L), although a level of 150 mg/dL (8.3

    mmol/L) is more commonly recognized as abnormal.






    Beta-2-adrenergic agents

    Beta-1-adrenergic blocking drugs


    Calcium channel blockers

    Cocaine and amphetamines




    Epinephrine (Adrenaline)




    Somatotrophin (Human Growth Hormone)



    Vacor (PNU)




    Diabetes mellitus

    Other endocrine disorders


    Stress with sympathetic system activation




    Moderate hyperglycaemia causes no symptoms.  At higher blood glucose

    concentrations, glucosuria leads to osmotic diuresis and dehydration. 

    Very high concentrations (greater than 600 to 800 mg/dL [33 to 44

    mmol/L]) can cause obtundation or coma as a result of serum



    Patients with drug-induced hyperglycaemia usually have other

    manifestations of the intoxication which help suggest the diagnosis. 

    For example, overdose of salbutamol (albuterol) or other

    beta-adrenergic agents causes tachycardia, widened pulse pressure,

    agitation, and hypokalaemia.  Similar findings may be seen with

    intoxication by caffeine or theophylline, both of which are also

    associated with seizures at high levels.  Calcium antagonists such as

    verapamil cause hyperglycaemia accompanied by hypotension and cardiac


    conduction defects.  Iron poisoning causes vomiting and diarrhea, and

    radiopaque iron tablets are often visible on abdominal radiographs. 




    Other causes of coma and dehydration including:


         Hypernatraemia (eg, diabetes insipidus)


         Hypovolaemia from vomiting, dehydration, etc.

         Ingestion of alcohols




    Rapid blood glucose measurement.  This may be performed by the

    hospital laboratory or at the bedside using fingerstick capillary

    blood and a portable battery-operated analyzer or a test strip. The

    presence of glucose on dipstick testing of the urine suggests an

    elevated blood glucose concentration.

    Serum electrolytes

    Serum ketones

    Renal function tests (urea, creatinine)




    In general, drug-induced hyperglycaemia does not require treatment,

    and efforts can be focused on other manifestations of the specific

    overdose, such as treatment of shock or seizures.  For patients with

    evidence of dehydration, administer intravenous fluids (preferably

    normal saline). For significantly elevated blood sugar concentrations,

    consider intravenous insulin.




    Serum glucose levels should be monitored only if they are very high

    (greater than 19 to 22 mmol/L [350 to 400 mg/dL]).  Decisions about

    hospital admission and length of emergency monitoring will depend

    largely on the specific overdose.




    Not common. Permanent insulin-dependent diabetes mellitus may occur

    after poisoning by Vacor, pentamidine, alloxan or streptozocin.




    Author:        Dr K R Olson, University of California, San Francisco.


    Peer review:   Cardiff 9/96: V. Afanasiev, M. Burger, T. Della Puppa,

  1. Fruchtengarten, K. Olsen, J. Szajewski.


INTOX Home Page






    A serum sodium concentration greater than 145 mmol/L (mEq/L).




    Secondary to insufficient water intake

         CNS depression from toxic cause 

         Toxic delirium


    Secondary to excessive water loss

         Cholinergic syndrome with severe sweating 

         Drug-induced nephrogenic diabetes insipidus






         Severe gastroenteritis from toxic cause


    Secondary to excessive sodium ingestion

         Penicillins (some)

         Sodium Chloride

         Sodium Valproate 




    Diabetes insipidus

    Environmental exposure with dehydration

    Hyperglycaemia leading to osmotic diuresis

    Iatrogenic (hypertonic fluid administration, inadequate free water)

    Interstitial nephritis

    Polyuric phase of renal failure (eg, after relief of prolonged urinary





    Delirium and decreased level of consciousness may occur with severe

    hypernatraemia.  Associated illness or circumstances of exposure may

    result in hypovolaemia and hypotension.  Patients with heat exposure

    may also be hyperpyrexic.








    Serum sodium

    Serum potassium, chloride, and bicarbonate

    Renal function tests (urea, creatinine)

    Blood glucose (to exclude hyperglycaemia as a cause of free water


    Serum calcium and magnesium

    Urine sodium

    Urine osmolality (This is the most useful test to determine the cause

    of hypernatraemia.  Patients who are dehydrated but with normal renal

    function usually have an elevated urine osmolality [greater than 400

    mOsm/kg].  Patients with impaired ADH secretion or reduced

    responsiveness of the kidney to ADH, will usually have a urine

    osmolality of less than 250 mOsm/kg.)




    Use caution, as overly rapid correction of serum sodium can lead to

    cerebral oedema.  The goal of treatment should be to correct the serum

    sodium at a rate no faster than 1 mmol/L/hour or 25 mEq/L/day.  In

    asymptomatic patients, a rate of 0.5 mmol/L/hour is acceptable. 

    Obtain frequent measurements of the serum sodium and adjust treatment



    Patients with hypovolaemia should be initially treated with

    intravenous isotonic saline.  Once volume is restored, this should be

    changed to half-normal saline with dextrose.


    Patients with normovolaemic hypernatraemia may be treated with oral

    water administration or intravenous 5% dextrose solution.  Patients

    who are hypervolaemic may need a loop diuretic such as  furosemide to

    remove excess volume. 


    Patients with lithium-induced nephrogenic diabetic insipidus who do

    not improve after discontinuation of lithium may be treated with

     indomethacin, 50 mg every 8 hours, and  hydrochlorothiazide 50 to

    100 mg/day. 




    Follow volume status and electrolytes carefully, and avoid overly

    rapid correction of the serum sodium.  Patients should be monitored

    for altered mental status and coma.




    Overly rapid correction of hypernatraemia may cause cerebral oedema

    and permanent brain damage. 




    Author:        Dr Kent R. Olson, University of California,

                   San Francisco, USA (February 1999).


    Reviewers:     Birmingham 3/99: B Groszek, H Kupferschmidt,

                   N Langford, K Olson, J Pronczuk.