Chemicals & Cancer: Establishing Causation
By Nachman Brautbar, M.D.

About The Author:

Dr. Nachman Brautbar specializes in Internal Medicine, Occupational Medicine and Toxicology. He is a Clinical Professor of Medicine and he is a member of the American Society of Toxicology, the American College of Toxicology, and the American Society of Internal Medicine. He has published over 215 scientific peer reviewed papers and book chapters in the fields of Toxicology, Pharmacology, Internal Medicine, Immunology and Nephrology. Dr. Brautbar is a treating physician and in his practice he addresses such issues as the use and effects of the drug Phen-fen, in addition to lung disease, asbestosis, chemical injury, solvent-related toxicity, occupational diseases, and quality of care in hospitals, offices & nursing homes. Dr. Brautbar has testified as an expert in some major toxic torts nationally.

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INTRODUCTION

Chemical exposure and cancer date back several thousand years. The famous occupational physician, Ramazzini, was one of the first to describe examples of occupationally-induced cancers.

In the last 20 years, benzene has been shown to be a carcinogenic agent causing leukemias, lymphomas, and other hematological cancers. Other chemicals, such as chlorinated hydrocarbons, asbestos, and hexavalent chromium, have been shown to be carcinogenic.

The observation that despite reduction in cigarette consumption, despite reduction in fatty food consumption and despite improved screening procedures, cancers of the lung, breast, and blood system is on the rise and is by and large attributed to a combination of environmental chemical factors imposed on the genetic makeup of the individual.

I. CAUSATION - DEFINITION

Causation, meaning cause and effect, is one of the most important and complex duties a forensic-medicolegal examiner has to establish. As physicians practicing medicine, we have been trained to think etiology of a disease which does not necessarily mean causation. The training in medical school, internship residency and fellowship always addressed etiology synonymously with causation, but we were not taught the practical meaning of the word causation.

The medical scientific community has been struggling with this issue of causation since the early days of Paracelsus. The first criteria for causation were established by Henle and Koch when Henle and his students, including Koch, studied cholera in the 1880's. These criteria have changed through the years undergoing natural evolution. With new discoveries, Henle and Koch's criteria were no longer valid for viruses and cancers. In the 1960's Sir Bradford-Hill, who studied the cancerous effects of cigarettes, nickel and others, presented his criteria to establish medical causation. These criteria have been endorsed by the scientific community and utilized in occupational medicine and toxicology.(1)

II: THE ROLE OF EPIDEMIOLOGICAL STUDIES

It is important to remember that epidemiological studies and their interpretation may not be acceptable by law for a specific case. Since epidemiological data apply to populations, they mean that a probability that an association between variables is statistically significant and therefore, that association may be causality. Since most medicolegal assessment of causation apply to one individual, we can not extrapolate risks based upon studies of populations to determine the risks faced by a particular individual.(2) While epidemiological data might support the assessment of causation in one individual, the courts have not accepted epidemiological data as a probable explanation of causation for one case in general.

Epidemiology has been used to assess causation in toxic exposure. While epidemiological data may serve as a preliminary suggestion of a statistical association, they cannot address dose response, latency period, low level chronic exposure and genetic make-up of the individual. Usually no single study can be considered strong enough to prove causation in an exposure case, unless additional criteria can be shown, and conversely, several studies that fail to show a statistical association do not disprove a causative role for a given exposure.(3)

To the medicolegal examiner, there might seem to be a confusion between the legal and epidemiological criteria of causation. Indeed, it is not unusual to see opposing counsel asking the expert in a deposition, "Doctor, you opined that there is no absolute proof that Mr. Gerald's cancer is the result of his exposure to Benzene at work. Can you kindly translate this into statistical percentage?" (Clearly, the skilled attorney wants to show that the doctor is using an unreasonable standard.) He is waiting for the doctor to answer, "Yes, statistically I like to see 95% proof." This answer is great for the deposing attorney because he is going to show to the court that the doctor is not using the legal standard of reasonable probability (51%), but is unreasonable and wants 95%. We must remember that in the legal arena the expert must address reasonable probability, more likely than not, measuring 51% likelihood that a certain exposure caused a certain disease, based on the Bradford-Hill criteria.

To confuse matters more, to determine causation in a specific case, the medicolegal examiner must also remember that there are several causes and at times, many causes for a specific disease. Not only must the examiner use 51% probability based on the Bradford-Hill criteria, the cause must be the proximate to the disease in question.

III. SCIENTIFIC CRITERIA FOR ESTABLISHING CAUSATION

A. Application Of Animal Studies To Human Cancers.

Some chemicals cause cancer in experimental animals. Those chemicals identified as being causally associated with cancers in humans, have all been shown to produce cancer in laboratory animals. In every instance, as least one site of cancer was common to both animals and humans. (5,6)

This knowledge, together with the similarities in mechanisms of carcinogenesis across animals and humans, led to the scientific logic that chemicals shown to be carcinogenic in at least 2 species of animals should be considered as being likely to present cancer risks to humans. (7,8)

Dr. David Rall from NIOSH clearly summarized the scientific evidence for admissibility of animal carcinogenesis in addressing causation in human cancer: "Experimental evidence indicates that there are more physiological, biochemical, and metabolic similarities between laboratory animals and humans than there are differences. These similarities increase the probability that results observed in a laboratory setting will predict similar results for humans." Clearly, the accumulated experience in the field for carcinogenesis supports this concept.(9)

Dr. David Rall's peer reviewed publication clearly supports the scientific policy of the International Agency for Research on Cancer and the current opinion in carcinogenesis that agents shown to be carcinogenic in animals, but do not have safety studies in humans, present a carcinogenic risk to humans.

B. Chemicals Proven To Be Carcinogenic In Human Studies

Chemicals shown to be carcinogenic in experimental animals are shown to be carcinogenic in humans. Chemicals are identified that were first shown to cause cancer in laboratory animals and were subsequently found to be associated with cancers in humans. The source for this information comes from IARC Monograph Series and the National Toxicology Program Report as well as the Department of Health and Human Services' reports on carcinogenesis. The following are chemicals that were initially shown to be cancer-causing in animals and subsequently in humans:

Table 1. Chemicals And Cancer In Humans:

Chemicals possibly or probably associated with cancer in humans:

1. Acrylonitrile
2. Aflatoxins
3. 4-Aminobiphenyl
4. Analgesic mixtures with phenacetin
5. Asbestos
6. Beryllium
7. bis(chloromethyl) ether
8. 1.3-Butadiene
9. Cadmium
10. Chlorinated + by products
11. DDT and related compounds
12. 1Diethylstillbestrol
13. 1Dibromoethane
14. 1Ethyl acrylate
15. Ethylene oxide
16. 1Formaldehyde
17. Gasoline
18. 1Glass wool
19. Lead and lead compounds
20. Melphalan
21. 8-Methoxyssoralen + UV radiation
22. 24,4-Methylene bis(2- Chloroanilene)
23. 24,4-Methylene Dianiline diHCl
24. 2Mustard Gas
25. Ochratoxin A
26. 2Phenacetin
27. Radon Gas
28. Silica, crystalline
29. 2,3,7,8-TCDD
30. Vinyl chloride
31. MTBE
32. Trichloroethylene

C. Material Safety Data Sheets And Regulatory Agencies

IARC has identified fifty-nine agents that are recognized and widely accepted as being irrevocably linked to human cancers that can be collated into five groups, eight single chemicals, ten groups of mixture of chemicals, nineteen individual or combination of pharmaceuticals, thirteen industrial processes or occupations, and nine environmental or cultural lifestyle risk factors.

Commonly defendants will tell you that they have reviewed material safety data sheets and although a chemical may be carcinogenic for animals, "is not carcinogenic for humans." These statements are commonly not supported by scientific evidence and can be easily discounted if your expert knows the studies by IARC, NTP (National Toxicology Program) and DHSS (Department of Health and Human Services).

Because epidemiological data is often absent or past exposure data are unavailable, public health decisions must continue to be largely based on animal data. Historically, this logical concept is served to the public as well as preventive medicine. Thus, in assessing cause and effect with human cancer, these chemical carcinogenesis results in laboratory animals frequently, if not almost always, constitute the primary basis for identifying and protecting potential human health hazards.(10,11)

This policy is clearly manifested in EPA Regulations stating, "Ideally, evidence regarding the effect on humans would be the best data, but federal agencies have found that limitations in the ability to derive epidemiological data have made such data a relatively unreliable protector from most substances. As a consequence, the accepted scientific approach is to examine, evaluate and integrate all available animal, chemical and epidemiological data."(12)

D. Level Of Exposure

For those chemicals, mixture of chemicals or undefined circumstances in which humans are exposed to known or potential carcinogens, the hallmark public health issue centers on whether the level of exposure, if any, will present little or no carcinogenic risk to the individuals or populations in unprotected or uniform conditions. (13,14,15)

The International Agency for Research on Cancer (IARC) holds the position that carcinogenic agents that do not possess any data to support safety levels in humans, do not comply with threshold and therefore no safe level of exposure exists. One of the most typical is benzene. The most recent position paper of the Collegium Ramazzini, which is a highly prestigious occupational medicine and toxicology scientific association, clearly indicated that, "there are no safe levels of exposures to benzene or asbestos". Therefore, do not let yourself be misled by a smoke screen of "levels". Make sure that your expert clearly understands the issue of levels, is well aware of the literature and can respond to such challenges by the defendants. The concept of safe exposure level to a carcinogen accepts the erroneous concept of threshold.(16)

The California Supreme Court in its recent Rutherford decision (regarding asbestos exposure) addressed the issue of levels of exposure and decided that "significant levels" of exposure equalled to any levels which are not "theoretical" or "infinitesimal".

E. Medical And Forensic Application Of Regulatory Levels

Commonly, even if the material safety data sheets indicate injurious carcinogenic exposure and even if the job analysis description or environmental measurements indicate measurable levels of the carcinogenic agent in the air or the water, the defendants will come back with the notion of TLV, which is the Threshold Limit Value or the notion of allowed levels of exposure by various governmental agencies, such as NIOSH or OSHA. Those levels apply only to the normal population, meaning that these regulatory levels do not apply to individuals with genetic diseases, liver conditions, smokers, individuals with lung conditions, elderly individuals, individuals with metabolic health conditions, individuals with variable nutritional intakes. Therefore, these levels apply only to 66% of the population and do not take into account 34% of the population. Furthermore, for a specific case the expert should use the scientific evidence and the preponderance of evidence to conclude causation (51% probability).

F. What Does The Expert Need In Order To Establish Causation?

Defendants commonly uses the tactics of, "there are no epidemiological studies", or, "there is no statistical evidence to show causation for a certain chemical". The United States Supreme Court in it's Daubert's decision addresses that issue and concludes that the expert has to provide scientific opinion, based on methods and techniques generally used, and/or relying on peer reviewed publications for testability of his opinion that causation is more likely than not due to the chemical in question (51% probability). The expert does not necessarily need to rely on epidemiology, or scientific certainty "or provide scientific proof," but rather follow the above quoted guidelines applied in the U.S. Supreme Court Daubert decision. The expert should know the accepted methodology to establish causation described in the scientific and medical literature,(1) and established originally by Sir Bradford-Hill.(17) These criteria are the cornerstone of establishing causation, and are described as follows:

1. Strength of the Association. This quality has two aspects: the frequency with which the factor is found in the disease, and the frequency with which it occurs in the absence of the disease. Since most diseases have more than one determinant, we cannot expect complete correspondence between the factor and the disease. The larger the relative risk, however, the more the hypothesis is strengthened.
2. Consistency. Confirmation of the association by different investigators, in different populations, using different methods.
3. Dose-Response Relationship. Finding a quantitative relationship between the factor and the frequency of the disease. The intensity or duration of exposure may be measured.
4. Chronological Relationship. Obviously, exposure to the factor must occur before onset of the disease. In addition, if it is possible to show a temporal relationship, as between exposure to the factor in the population and frequency of the disease, the hypothesis is somewhat strengthened.
5. Specificity. If the determinant being studied can be isolated from others and shown to produce changes in the incidence of the disease, e.g., if bladder cancer can be shown to have a higher incidence specifically associated with a particular industrial chemical, rather than with work in an industry (or other exposure such as tobacco), this is convincing evidence of causation.
6. Biological Plausibility. Sometimes, the statistically significant association fits well with previously existing knowledge, for example, when various aniline dyes were found to be associated with increased incidence of bladder cancer. This criterion should be used with caution, however – it could impede development of new knowledge that does not fit existing ideas.
7. Coherence. The evidence must fit the facts that are thought to be related, e.g., the rising incidence and mortality rates from lung cancer and the rising consumption of tobacco in the form of manufactured cigarettes are coherent.
8. Experiment. Although it is unethical to do an experiment that exposes people to the risk of illness, it is permissible, indeed desirable, to conduct an experimental, i.e., a randomized controlled trial, on control measures. If an environmental toxin is suspected of causing neurological symptoms, for example, the experiment of eliminating or reducing occupational exposure to the toxin and conducting neurological tests on the workers could help to confirm or refute the suspicion.
9. Analogy. With an unequivocal example like thalidomide as a cause of gross congenital abnormality, we would be justified in suspecting other substances found to be less strongly associated with congenital malformation.

These criteria serve as a general guide, and are not meant to be an inflexible list. Not all criteria must be fulfilled to establish scientific causation.(1) The key criteria required to establish causation are commonly 1) temporal relationship, 2) specificity, 3) biological plausibility, 4) coherence.

While I recognize that the workers' compensation system has its' exclusive remedy and was originally designed as a no fault system, relying on medical scientific criteria and understanding the important role that we play in defining causation will certainly help all parties involved in this system. I believe that it is appropriate to close this manuscript by quoting Dr. Rivers, 1937, "To obtain the best results, however, this ingenuity must be tempered by the priceless attributes of common sense, proper training, and sound reasoning."

SUMMARY

Chemical carcinogenesis is common and plays a significant role in morbidity and mortality in the workers' compensation arena. To establish causation your expert needs:

1. Exposure history.
2. Material safety data sheets or testimony in regards to chemicals used (such as deposition of the company's safety officer).
3. Medical records establishing the diagnosis.
4. Rely on literature describing carcinogenesis from the chemical in question in either animals or humans.
5. Use "reasonable" medical probability, temporal relationship, and exposure to injurious chemicals.

ACKNOWLEDGMENT

The author wishes to thank Ms. S. Loomis for her tireless work in transcribing this manuscript.

REFERENCES

1. Rom, W.N, "Causation". Textbook of Environmental and Occupational Medicine, 2nd Edition, 1992
2. Maxcy-Rosenau. Public Health and Preventive Medicine, 12th Edition, 1992
3. Karns, M.E. Trial. 46-52, 1994
4. Daubert v. Merrill Dow Pharmaceuticals. (1993) 509 U.S. 579, 113 S. Ct 2786
5. Tomatis, et al, Annals of Review of Pharmacology and Toxicology, Vol. 19, pages 511-530, 1979
6. Huff, et al, Maxcy-Rosenau-Lasts, Public Health and Preventive Medicine Textbooks, 13th Edition, Appleton & Lang, Norwalk, CT, 1992, pages 433-440 and 453-457
7. IARC Monograph on the Evaluation of Carcinogenic Risks to Humans, Overall Evaluations of Carcinogenicity, Update of IARC Monograph, Vols, 1-42, Supplement 7, International Agency for Research of Cancer, Lyon France, 1987
8. IARC Monographs on the Evaluation of Carcinogenesis Risks to Humans, Vols. 1-54, International Agency for Research on Cancer, Lyon France, 1972-1992
9. Rall, et al, Annual Review of Public Health, 1987, Vol. 8, pages 355-385
10. Ota, Assessment of Technologies for Determining Cancer Risks from Environmental. Office of Technology Assessment, Congress of the United States, Washington, D.C., 1981
11. Huff, et al, Scandinavian Journal of Work Environmental Health, Vol. 18, Supplement 1, pgs 31-37, 1992
12. EPA Regulation A, 1991
13. Huff, et al, Annals of the New York Academy of Sciences, Vol. 534, pgs 1-30, 1988
14. National Research Council, Risk Assessment in the Federal Government, Managing the Process, National Academy Press, Washington, D.C., 1983
15. Tomatis et al, Cancer Causes: Occurrence and Control, IARC Scientific Publication, No. 100, International Agency for Research on Cancer, Lyon France, 1990.
16. Office of Science and Technology, Staff Group on Chemical Carcinogenesis, Chemical Carcinogens: Federal Regulations, Vol. 50, 10371210442, 1985, Published in Environmental Health Perspective, 1986, Vol. 67, pgs 201-282
17. Hill, A.B. "The Environment and Disease: Association or Causation?" President's Address. Proc Royal Soc Med. 1965 9:295-300.

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