Evaluation of Potential Carcinogenic Hazard - Advances in Chemistry

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C. J E L L E F F CARR and A L B E R T C. K O L B Y E , JR. The Nutrition Foundation, Inc., Washington, D C 20006 To evaluate potential hazards to public health posed by environmental chemicals, the specific configuration of biological characteristics of each chemical should be considered in the context of dose-response data and knowledge concerning mechanism of biological action. Absorption, metabolism, and excretion-storage data provide insight into toxicity and detoxification. Short-term tests in vitro and in vivo can help to clarify (within the limits of present knowledge) whether the compound in question is an initiating carcinogen (self-promoting at more substantial doses; i.e., a “complete” carcinogen) or is more likely to be a “promoter” or enhancer of carcinogenesis mediated by discernible toxicity to organs, systems, or tissues. The pattern of exposure and dosage is an important determinant of outcome as is the degree to which biological resistance can withstand or repair the biological damage that is a critical prerequisite to cancer.

- E X P E R I M E N T S U S I N G L I F E T I M E A N D SUBCHRONIC EXPOSURES in laboratory

animals to evaluate the toxicological characteristics of test substances have assumed an increasing scientific and societal importance. The data from these experiments are used in a variety of ways to make qualitative and quantitative judgments concerning potential hazards to human health when humans are exposed to these test substances. The accuracy and relevance of test data derived from animals become of paramount importance when public health considerations and judgmental interpretations for safety are involved. Substantial biological differences and variations of response to carcinogenic agents exist among the species, genetic strains, sexes, and subsequent generations of laboratory animals. Their responses are governed also by environmental factors such as stress, diet, and multiple chemical exposure. Recently, the published results of these carcinogenicity bioassays have been widely criticized on the basis of the methodology employed, including improper use of the maximum tolerated dose (MTD), excessive dosage by oil gavage of water-insoluble substances, and inattention to key nutrients in chronic animal studies lasting at least 2 years. 0065-2393/85/210/0335$06.00/0 © 1985 American Chemical Society

Turoski; Formaldehyde Advances in Chemistry; American Chemical Society: Washington, DC, 1985.

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on May 15, 2018 | https://pubs.acs.org Publication Date: August 21, 1985 | doi: 10.1021/ba-1985-0210.ch022

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FORMALDEHYDE: A N A L Y T I C A L CHEMISTRY A N D TOXICOLOGY

Many of these issues have been reviewed by the Ad Hoc Panel on Chemical Carcinogenesis Testing and Evaluations to the National Toxicology Program Board of Scientific Counselors, and substantial recommendations for future changes have been made (J). However, for the immediate past and the present we are confronted with numerous difficult decisions that will, in large measure, determine current regulatory actions. A growing concern exists in regard to the salient factors of pharmacokinetic mechanisms, target-cell concentrations, metabolism, and excretion of test substances in carcinogenicity assays. These factors are now recognized to influence significantly the outcome of these tests, including such biological processes as the formation of chemically reactive metabolites, inhibition of enzyme mechanisms, and covalent binding to cell components that may or may not account for genetic or what are said to be "nongenetic" effects. Numerous literature references have been made to the significance of determining when the doses in the chronic toxicity tests exceed the animal's metabolic capacity. These subsequent, untoward, confounding effects have been noted in the Nutrition Foundation's review of the effects of using vegetable oils as vehicles (2). Such high doses exceed the metabolic "break point," and as a consequence high tissue concentrations of the test material are produced. This result can cause nonspecific toxic challenges that represent a series of phenomena substantially related to the process involved with tumor promotion by classical promoters. This effect may be characterized as toxic hyperplasia. Toxic hyperplasia can increase tissue susceptibility to the initiating influence of carcinogenic compounds by increasing the susceptibility of cells to electrophilic attack (3). As has been shown, cellular injury of a nonspecific nature can impair the functioning of protective cellular enzymes, and the result is a further increase in the local concentration of the active chemical moiety. Proteins are denatured, membranes are destabilized, and normal cellular processes cease to function, such as the active and passive transport of cellular components. The net result is the potential for attack on the DNA and RNA by genotoxic agents. Unfortunately, the role of nonspecific toxicity per se in relation to carcinogenicity has been poorly appreciated in the entire field of cancer studies (3). Scientists have little doubt that numbers of toxic substances can be shown to be carcinogenic when massive doses are administered. The significant issue is the relevance of these findings to the much smaller amounts of human exposure that can be detected by exquisitely sensitive analytical techniques. Unfortunately, carcinogenicity studies are not terminated when the M T D dosage proves to be too high on the basis of preliminary short-term tests. Therefore, the final test data remain equivocal and are the subject of criticism from a toxicological standpoint.


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The pharmacokinetics and metabolism of chemical substances may be distinctly different depending on low or high doses (4). The issues of adequate dosage schedules have been reviewed with recommendations by numerous advisory groups (J, 5). For example, the American Industrial Health Council's position was stated as follows (5): Bioassays using the maximum tolerated dose administered via unexpected routes of exposure have not been selective in distinguishing chemicals for regulation as carcinogens, and furthermore, such studies provide very little guidance for risk assessment. The Potential Carcinogenic Hazard of Formaldehyde On the basis of these general considerations, one may ask a series of questions regarding the extensive and elaborate studies conducted to estimate the human cancer risk from formaldehyde. Certainly the enormous amount of industrial, scientific, analytical chemical, and regulatory expertise that has been and continues to be devoted to this overwhelming task is worthy of our best efforts to find satisfactory answers to these penetrating questions. Our questions should concern the epidemiological, physiological, and toxicological data on formaldehyde as they pertain to the analysis and evaluation of carcinogenic risk. The answers will permit risk assessment procedures and risk management decisions to be made on the basis of all relevant biological information. How persuasive are the data from the animal bioassays for carcinogenicity? Reference has been made to some of the criticisms of these test methods. A recent review concludes that the risk at low-level exposure would not be linearly related to the risk found at the higher levels observed to be carcinogenic in animals (6). Animal studies demonstrated that formaldehyde is carcinogenic in the nasal cavities of rodents in cytotoxic doses inhaled and causes increased cellular proliferation. But lower levels are not carcinogenic. Major anatomical differences exist between the nasal cavities of humans and those of most animals; for example, rats and mice are obligatory nose breathers (7). Is it proper to equate inhalation studies in these rodents to humans? Cellular Toxic Effects of Formaldehyde Formaldehyde in high concentrations is a protoplasmic poison and is primarily an irritant as a result of its protoplasmic coagulating action. This cellular effect accounts for many of its uses, but from the standpoint of carcinogenicity, it introduces the question of a kind of nonspecific chemical burn. There would be some protection against this effect by inhalation because sensory irritation in the respiratory tract has a lower threshold than cellular alterations, and this condition would tend to avoid cytotoxic-



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ity unless animals are required to breath the vapors in high doses. From the standpoint of carcinogenicity assessment, the question remains of the significance of the cellular degeneration, necrosis, and inflammation produced by formaldehyde in adequate doses. These are levels that have been observed to cause increased cell proliferation (8) and acute degeneration, necrosis, and inflammation (9, 10), believed to be critical events in formaldehyde carcinogenesis. These characteristics of a substance have regulatory implications and must be included in the decision process because biochemical toxicity patterns vary with the specific chemical as has been pointed out. In the body, formaldehyde is metabolized and contributes to the formate pool. It can enter into the metabolism of one-carbon compounds and give rise to methyl groups (II). In vitro preparations of liver enzymes convert the aldehyde to formic acid, and the variations of these metabolic changes largely involving aldehyde dehydrogenase have been studied in detail. Dealkylation of numerous drugs such as codeine, ephedrine, and phenacetin yield formaldehyde by the action of the microsomal enzyme systems of the liver. In addition, formaldehyde is a normal metabolite and enters into the chain of biochemical events in humans and other animals to give rise to essential cellular substances (12). For these reasons formaldehyde is not considered a toxic cellular component in low concentrations. The Scientific Committee of the Food Safety Council devoted 4 years to the preparation of a report entitled, "Proposed System for Food Safety Assessment" (13). This unique report has been acknowledged as a most definitive one in the field of toxicity assessment of food ingredients. The committee's system included the important decision that if a metabolite or a test substance proved to be a normal body constituent, it would be considered safe, and only the quantity consumed or formed in the body would be an issue to be resolved. It appears that formaldehyde meets this decision criterion. Insofar as cellular toxic effects are concerned, we are confronted with the question of how shall we differentiate occasional low-level exposure to formaldehyde versus prolonged occupational exposure? Carcinogenic Mechanisms Several comprehensive reviews have addressed the question of the genotoxicity of formaldehyde (9, 10, 14-16). Mutations based on short-term in vitro tests have been reported, but not all tests were positive. Although conflicting results have been obtained, it is not clear whether these changes would follow noncytotoxic doses. Can formaldehyde be considered mutagenic or capable of inducing chromosomal aberrations for humans if these effects have not been demonstrated in intact mammalian systems following inhalation? In other words, is it really a truly genotoxic agent? Therefore, as pointed out by Carlborg (17), is linear risk extrapolation justified? Such a


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low-dose linear risk assessment can be made for truly genotoxic agents that operate to damage DNA at subtoxic doses for which no other detectable biological endpoints are observable.


Epidemiologic Evidence Because the primary route of exposure to formaldehyde for humans is through inhalation, one might expect the upper respiratory tract to be the chief target tissue. By using C-labeled formaldehyde in rats, the upper respiratory tract has been shown to be the major absorption site (18). Indeed, toxic levels induce squamous cell carcinomas in the nasal cavities of rats and mice. For these reasons, in exposed populations one might expect to find an increased incidence of tumors of the nasal and nasopharyngeal epithelium if formaldehyde were carcinogenic to humans. This issue has been reviewed by Squire and Cameron (6), and they concluded that nasopharyngeal cancer is an uncommon disease in the Western world. Case-control and cohort studies have been reported by numerous investigators, and two review bodies have studied the evidence. The conclusion reached was that although formaldehyde gas can be considered carcinogenic for rats, inadequate evidence existed to evaluate its carcinogenicity to humans (9, JO). The Federal Panel on Formaldehyde (19) concluded that presumption of formaldehyde being carcinogenic in humans exists, but lack of information on exposure and confounding factors of multiple exposures hampered the interpretation of the data. 14

Conclusion Certain carcinogenesis studies should be repeated to take into consideration the methodology issues now recognized to significantly influence test results. With more reasonable and verifiable scientific data, public health decisions concerning estimations of risk to humans from ingestive or inhalation exposures could be made on a much sounder scientific basis. Humans are ingesting, and have always ingested, large amounts of many natural substances that might influence cancer risk. Everyone agrees that the public ought to be protected from new and additional significant environmental risks, but such decisions should be realistic and based on sound, agreed-upon scientific data. We cannot afford to make rash decisions or decisions by panic that erode public confidence in the regulatory process and impose tremendous economic turmoil if the actual benefit to public health is disproportionally small. Literature Cited 1. National Toxicology Program, Ad Hoc Panel on Chemical Carcinogenesis Testing and Evaluation Report, Feb. 15, 1984. 2. The Nutrition Foundation, Ad Hoc Working Group Report on Oil-Gavage in Toxicology, July 14-15, 1983.


340 3. 4. 5. 6. 7.


8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.


Kolbye, A. C., Jr. Reg. Toxicol. Appl. Pharmacol. 1982, 2, 232-37. Watanable, P. G.; Gehring, P. J. Environ. Health Perspect. 1976, 17, 145-52. Moolenaar, R. J. Reg. Toxicol. Appl. Pharmacol. 1983, 3, 381-88. Squire, R. Α.; Cameron, L . Reg. Toxicol. Appl. Pharmacol. 1984, 4, 107-29. Proctor, D . F.; Chang, J. C. F. In “Nasal Tumors in Man and Animals”; Reznik, G . ; Stinson, S. F.; Eds.; C R C : Boca Raton, Fla., 1983. Swenberg, J. Α.; Gross, Ε. Α.; Martin, J.; Popp, J. A. In “Formaldehyde Toxic ity”; Gibson, J. E . , Ed.; Hemisphere: Washington, D . C . , 1983. IARC Monogr. Eval. Carcinogen. Risk Chem. Man 1982, 29, 345-89. IARC Monogr. Eval. Carcinogen. Risk Chem. Man 1982, 29, 391-98. Williams, R. T. “Detoxication Mechanisms: The Metabolism and Detoxication of Drugs, Toxic Substances, and Other Organic Compounds,”2d ed.; Wiley: New York, 1959; pp. 88-90. Committee on Aldehydes, National Research Council “Formaldehyde and Other Aldehydes,”NAS: Washington, D . C . , 1981. Food Safety Council “Proposed System for Food Safety Assessment,” Washing ton, D . C . , 1980. Auerbach, C . ; Moutschen-Dahmen, M.; Moutschen, J. Mutat. Res. 1977, 39, 317-62. Formaldehyde Institute, Report on the NCTR Consensus Workshop on Formal dehyde, Scarsdale, N.Y., November 1983. Clary, J. J.; Gibson, J. E . ; Waritz, R. S. “Formaldehyde: Toxicology, Epidemi ology, and Mechanisms”; Marcel Dekker: New York, 1983. Carlborg, F. W . In “Formaldehyde: Toxicology, Epidemiology, and Mecha nisms”; Marcel Dekker: New York, 1983; pp. 31-45. Heck, H . D.; Chin, T. Y.; Schmitz, M . C. In “Formaldehyde Toxicity”; Gibson, J. E . , E d . ; Hemisphere: Washington, D . C . , 1983. Federal Panel on Formaldehyde EHP, Environ. Health Perspect. 1982, 43, 13968.

RECEIVED

for review September 28, 1984. A C C E P T E D December 19, 1984.


Evaluation of Potential Carcinogenic Hazard - Advances in Chemistry

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