In April 1996, the U.S. Environmental Protection Agency (EPA) published "Proposed Guidelines for Carcinogen Risk Assessment," the first revision of the original guidelines that were published ten years earlier. The proposed guidelines take into consideration the complexities of the carcinogenic process and the rapid pace of ongoing research and aims at making more scientifically based assessments of the carcinogenic potential of chemical and physical agents with an emphasis on using mode-of-action information to project dose-response relationships. To date a final version of the guidelines has not yet been published.

To understand how EPA assesses the risk posed to humans from exposure to chemical carcinogens, it is important first to understand

the process of carcinogenesis itself;

how potential carcinogens currently are identified (i.e., carcinogen testing); and

the problems in evaluating, interpreting, and extrapolating results from cancer studies in animals to potential carcinogenic effects in humans (i.e., risk assessment).

Although the exact cause(s) or mechanism(s) of carcinogenesis remains elusive, cancer is believed to involve a two step process -- initiation followed by promotion. For the initiation stage, most chemical carcinogens require metabolic activation by drug-metabolizing enzymes to form chemically reactive forms. These metabolically activated forms of carcinogens strongly and irreversibly bind to cellular macromolecules, such as DNA, RNA and proteins. That DNA, the genetic material, is the main molecular target for activated carcinogen interaction is increasingly evident, but as yet there is no conclusive proof that this is so.

Exposure of a normal cell to an "initiator" (i.e., a chemically reactive form of a carcinogen) alone is not sufficient to cause cancer. For cancer to occur the initiated cell then must be exposed to a promoter (i.e., a non-carcinogenic substance that acts on an initiated cell) to complete the two-step process of carcinogenesis. Initiators and promoters are not carcinogens since by themselves, they do not cause cancer. It is this dual process--initiation followed by promotion -- that forms the working hypothesis for carcinogenesis and on which scientific research is based.

Initiated cells may exist through numerous cell divisions without ever being transformed to cancerous cells. Since people may be exposed to substances in the environment that act as initiators, there is a strong likelihood that some cells in the body may be in an initiated or activated state. However, cancer will not occur unless the initiated cells are exposed to a non-carcinogenic promoter and complete the process of carcinogenesis. In the absence of exposure to a promoter, initiated cells remain dormant and do not progress to cancer. While exposure of normal cells to either initiators or promoters alone does not cause cancer to an appreciable degree, exposure to a "complete carcinogen" (often referred to simply as a "carcinogen") is sufficient for cancer to occur since complete carcinogens have the ability to both initiate and promote.

Categorizing Carcinogens

About 25 years ago, Drs. John and Elizabeth Weisburger of the National Cancer Institute (NCI) of the National Institutes of Health (NIH) began testing many commercially available, high production volume chemicals for their ability to cause cancer in laboratory animals. The Weisburgers devised a testing scheme that involved the administration of chemicals at very high concentrations to both sexes of mice and rats over their lifetime, then examining the animals for the presence of tumors. The incidence of tumors in rodents treated with the test chemical (i.e., "treated groups") then was compared with that in unexposed rodents (i.e., "control group"). What began as a research project eventually became a multimillion dollars Federal program known as the National Toxicology Program (NTP). The National Institute of Environmental Health Sciences (NIEHS) of the NIH currently manages this complex cooperative program between various agencies of the Federal government.

The Weisburgers's methodology for carcinogen testing (known as the "long-term animal bioassay") has been significantly improved over the years, but its basic premise remains the same. Namely, the administration of very high doses (i.e., "Maximum Tolerated Doses") of a chemical to both sexes of mice and rats for the lifetime of the animals as the best available method for identifying potential carcinogens.

Carcinogen Testing Methods

The long-term animal bioassay is difficult and expensive (more than a million dollars per chemical) and can yield ambiguous results. Yet, it is currently the best available method for identifying potential carcinogens. Because of the great expense, chemicals are rarely tested more than once in the long-term animal bioassay.

Some of the factors that must be considered when designing an animal bioassay include:

Test substance used (i.e., pure or commercial grade)

Species, strain and sex of animals used

Numbers of animals used (i.e., need an appropriate number to yield statistically meaningful results)

Route of administration (i.e., feed, water, injection, skin, inhalation)

Dosages and numbers of doses used (i.e., doses that are too high may lead to early deaths before tumors appear; those that are too low will result in insufficient amount of chemical administered to cause tumors)

Duration of exposure (i.e., lifetime or less than lifetime)

Animal husbandry (i.e., animals must survive to the end of the study or die from cancer) including genetic monitoring, health of the animals, feed, water, temperature and humidity, lighting, caging and sanitation

Randomization

Health and safety of personnel (i.e., personnel must wear "space suits" because the test chemical must be handled as if it is a carcinogen in humans)

Experts in toxicology and pathology are required

 

Short-term in vitro tests

Mutation -- i.e., the "Ames Test"

Chromosomal aberrations

DNA damage and repair

Sister chromatid exchange

Cellular transformation

 

These in vitro methods are used as a short-term screen for chemicals that interact with DNA and that require further investigation for their carcinogenic potential.

Other test methods

Induction of rat liver foci assay

Lung tumors in strain A mice bioassay

Rat mammary gland bioassay

SENCAR mouse skin tumorigenesis

Inhibition of intercellular communication

Alpha-fetoprotein as a marker of hepatocarcinogen exposure

Ornithine decarboxylase as a marker of carcinogenesis

Peroxisome proliferation as a marker of hepatocarcinogen exposure

When assessing what is the risk to people from their exposure to chemical carcinogens in the environment, most experts use a common-sense approach that looks at three specific factors -- hazard, potency and exposure.

Hazard -- the harm that a chemical might cause to humans. Hazard, such as the ability to cause cancer, is an inherent characteristic of the chemical. The long-term animal bioassay is the best currently available method for identifying carcinogenic hazard.

Potency -- a measure of how much of a chemical is needed to cause a particular hazard. For example, very small amounts of a very potent chemical carcinogen are required to cause cancer while larger amounts of a chemical carcinogen with low potency are required to cause a similar effect.

Exposure -- the amount of a chemical that actually comes in contact with the body, such as through food, water or air.

 

How much of the chemical is in the environment?

How much of the chemical reaches the target organ? and

How long the chemical remains active in the body?

Some chemicals are quickly eliminated from the body while others take a long time to be removed and bioaccumulate.

Hazard, exposure and potency are the three factors that make up "risk".

Risk -- the likelihood that a chemical will cause a specific hazard, such as cancer, in people. For example, a chemical carcinogen will pose no risk if people are not exposed to it, even if the chemical is a very potent carcinogen. A chemical carcinogen of low potency, however, may pose great risk if people are exposed to a lot of it.

By reducing exposure to a chemical carcinogen, people can reduce their risk from that chemical.

Understanding a chemical carcinogen’s potency and how it behaves in the body provides valuable information when determining any potential risk. Furthermore, by knowing how much of a chemical carcinogen reaches sensitive organs, scientists are able to determine whether the chemical can cause harmful effects in people.

Determining risk from chemical carcinogens is especially complicated since people are exposed to many potential chemical carcinogens in the environment at the same time. The effect of such a mixture of chemicals may be: (1) equal to the sum of the effects of the individual chemicals (i.e., "additive effect"); (2) greater than the sum of the individual effects (i.e., "synergistic effect"); or (3) less than the sum of the individual effects (i.e., "antagonistic effect").

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The Environmental Protection Agency (EPA) is the federal agency responsible for ensuring the safety of humans from exposure to potential chemical carcinogens in the environment. Scientists at the EPA use EPA's "Guidelines for Carcinogen Risk Assessment" to examine hazard, potency, exposure, dose-response and risk characterization (i.e., an analysis of all the available biological information on a chemical) to arrive at a determination of potential carcinogenic risk to humans. However, there are a number of practical considerations when arriving at a measure of risk, including:

Problem interpreting results from long-term animal bioassays

Route of administration of the chemical (i.e., was the route similar to that of human exposure?)

Doses used (i.e., extrapolating from high doses in the bioassay to low doses that people are exposed to)

Presence of chronic toxicity or other toxicological findings

Conduct of pathology and pathology review process

Significance of preneoplastic lesions

Statistical significance of the results; false positives and false negatives

Use of historical control data

Occurrence and significance of a decreased tumor incidence at some sites

 

Adequacy of the exposure assessment

Exposure assessment involves working with the key concepts of

Exposure

Intake

Uptake

Dose -- administered dose; applied dose; or internal dose

 

When the assessment was planned, what decisions were made about the purpose, scope, and level of detail or approach?

What are the exposure levels for the routes, pathways, and populations of interest?

How good is the assessment in terms of overall quality, degree of confidence in the estimates and conclusions, and strengths and weaknesses of underlying methodologies?

What additional research and data are needed to improve the exposure assessment?

 

Uncertainty analysis is a critical component of the overall analysis and presentation of exposure results.

Dose-response considerations

Risk characterization involves a knowledge as to what we know and what we don't know, and how confident we are about the ability to extrapolate from animals to humans and from high doses to low doses in each step of the risk assessment process. It further allows one to move away from the linear process of going from hazard to dose response to exposure to characterization and to begin to realize that exposure has a bearing on how one considers hazard and hazard has the ability to influence dose-response assessments.

Mechanistic information is used to inform hazard assessment, particularly as it relates to the relevance of animal data to humans. It is also used to understand the dose-response assessment and its relevance to protecting the most sensitive subpopulation, i.e., children.

Finally, the weight-of-the evidence approach is evaluated versus the strength of the evidence. All available studies, both positive and negative, are considered in the risk characterization step.

Classification of Carcinogens by the U.S. Environmental Protection Agency (EPA)

Group A: Carcinogenic to humans -- requires the observation of a statistically significant association between exposure to a substance and malignant or life-threatening benign tumors in humans.

Group B: Probably carcinogenic to humans -- the presence of limited evidence of carcinogenicity in humans (i.e., Group B1) or sufficient animal evidence, but inadequate human evidence for carcinogenicity (i.e., Group B2).

Group C: Possibly carcinogenic to humans -- the presence of inadequate human data, but the animal data demonstrate limited evidence of carcinogenicity (i.e., an increased incidence of benign tumors only; a positive finding of carcinogenicity in one species only; an increased incidence of tumors that occur with high spontaneous background incidence.)

Group D: Not classifiable as to human carcinogenicity -- insufficient data are available to make a determination as to carcinogenicity in humans.

Group E: Evidence of noncarcinogenicity for humans -- there is no increased incidence of tumors in at least two well-designed and well-conducted animal studies of adequate statistical power and dose in different species.

Hazard, potency and exposure are the pillars on which scientists base their safety assessment of environmental chemicals. Along with information on dose-response and risk characterization, a scientific conclusion is reached on the potential carcinogenic risk that a chemical might pose to humans. However, science is only one of the factors that managers at regulatory agencies use to make their final decision about the potential risk posed by exposure to a specific chemical and what is the best way to manage that risk. Economic considerations, engineering options and societal values, among others, are additional factors that are weighed in the "risk management" process.

Harry Milman, Ph.D.

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C. Heidelberger (1977), "Chemical carcinogenesis." Cancer, 40 (Suppl): 430-433.

U.S. Environmental Protection Agency (1986), "The risk assessment guidelines for carcinogens," Office of Health and Environmental Assessment, Washington, DC. EPA 600/S9-85/001F.

Committee of Risk Assessment Methodology, National Research Council (1993), "Issues in Risk Assessment," National Academy Press, Washington, DC.

H.A. Milman and E.K. Weisburger (1994), "Handbook of Carcinogen Testing," second edition, Noyes Publications, Park Ridge, NJ.

N.P. Page and co-workers (1997), "Implementation of EPA revised cancer assessment guidelines: Incorporation of mechanistic and pharmacokinetic data." Fund. Appl. Toxicol. 37:16-36.

I.F.H. Purchase and G.L.P. Randall (1998), "Principles of risk assessment." Pure and Applied Chemistry 70:1671-1683.

Miyamoto and W. Klein (1998), "Environmental exposure, species differences and risk assessment." Pure and Applied Chemistry 70: 1829-1845.

M.E. Andersen and co-workers (2000), "Lessons learned in applying the U.S. EPA proposed cancer guidelines to specific compounds." Toxicol. Sciences 53:159-172.

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TOXIC NOTES

Estrogen Likely To Be Listed As A Known Carcinogen

Every two years the National Toxicology Program (NTP), a branch of the National Institutes of Health, updates  its list of  proven and suspected cancer causing substances and publishes the results in the Biannual Report on Carcinogens.  In December of 2000 a panel of scientific advisors voted 8-1 that estrogen should be placed on the list of cancer causing substances, even though many women benefit from its use.

Over the last four decades thousands of studies and research trials have been conducted that positively link estrogen with cancer induction in animals and humans.  Scientists and physicians have long been aware of this adverse effect; however, the conventional thinking has been that the benefits for postmenopausal treatment and birth control far outweigh the risks.  The panel hopes that listing the substance in the known carcinogen category will force physicians to discuss the risks with their patients. 

Of the many thousands of chemical substances that are manufactured for use in the United States and worldwide only a tiny handful are listed as known carcinogens.  To be placed on the NTP list, there must be sufficient evidence of carcinogenicity from studies in humans which indicate a causal relationship between the agent and human cancer.  The panel anticipates moving steroidal estrogen to the known category in the next report, due out in 2002.  The current 9th Biannual Report on Carcinogens published by the NTP in 2000 can be accessed on the web at http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoc.html

©  2001 MEDICAL & TOXICOLOGICAL INFORMATION

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