Response letter from ACSH phthalate panel.
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Biomedical subjects
L S Gold
Publications and source records attributed to L S Gold.
Paracelsus to parascience: the environmental cancer distraction.
Entering a new millennium seems a good time to challenge some old ideas, which in our view are implausible, have little supportive evidence, and might best be left behind. In this essay, we summarize a decade of work, raising four issues that involve toxicology, nutrition, public health, and government regulatory policy. (a) Paracelsus or parascience: the dose (trace) makes the poison. Half of all chemicals, whether natural or synthetic, are positive in high-dose rodent cancer tests. These results are unlikely to be relevant at the low doses of human exposure. (b) Even Rachel Carson was made of chemicals: natural vs. synthetic chemicals. Human exposure to naturally occurring rodent carcinogens is ubiquitous, and dwarfs the general public's exposure to synthetic rodent carcinogens. (c) Errors of omission: micronutrient inadequacy is genotoxic. The major causes of cancer (other than smoking) do not involve exogenous carcinogenic chemicals: dietary imbalances, hormonal factors, infection and inflammation, and genetic factors. Insufficiency of many micronutrients, which appears to mimic radiation, is a preventable source of DNA damage. (d) Damage by distraction: regulating low hypothetical risks. Putting huge amounts of money into minuscule hypothetical risks damages public health by diverting resources and distracting the public from major risks.
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Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996.
The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of results of chronic, long-term cancer tests. This paper presents a supplemental plot of the CPDB, including 513 experiments on 157 test compounds published in the general literature in 1993 and 1994 and in Technical Reports of the National Toxicology Program in 1995 and 1996. The plot standardizes the experimental results (whether positive or negative for carcinogenicity), including qualitative data on strain, sex, route of compound administration, target organ, histopathology, and author's opinion and reference to the published paper, as well as quantitative data on carcinogenic potency, statistical significance, tumor incidence, dose-response curve shape, length of experiment, duration of dosing, and dose rate. A numerical description of carcinogenic potency, the TD(subscript)50(/subscript), is estimated for each set of tumor incidence data reported. When added to the data published earlier, the CPDB now includes results of 5,620 experiments on 1,372 chemicals that have been reported in 1,250 published papers and 414 National Cancer Institute/National Toxicology Program Technical Reports. The plot presented here includes detailed analyses of 25 chemicals tested in monkeys for up to 32 years by the National Cancer Institute. Half the rodent carcinogens that were tested in monkeys were not carcinogenic, despite usually strong evidence of carcinogenicity in rodents and/or humans. Our analysis of possible explanatory factors indicates that this result is due in part to the fact that the monkey studies lacked power to detect an effect compared to standard rodent bioassays. Factors that contributed to the lack of power are the small number of animals on test; a stop-exposure protocol for model rodent carcinogens; in a few cases, toxic doses that resulted in stoppage of dosing or termination of the experiment; and in a few cases, low doses administered to monkeys or early termination of the experiment even though the doses were not toxic. Among chemicals carcinogenic in both monkeys and rodents, there is some support for target site concordance, but it is primarily restricted to liver tumors. Potency values are highly correlated between rodents and monkeys. The plot in this paper can be used in conjunction with the earlier results published in the CRC Handbook of Carcinogenic Potency and Genotoxicity Databases [Gold LS, Zeiger E, eds. Boca Raton FL:CRC Press, 1997] and with our web site (http://potency.berkeley.edu), which includes a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency (TD50), and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Two summary tables permit easy access to the literature of animal cancer tests by target organ and by chemical. For readers using the CPDB extensively, a combined plot on diskette or other format is available from the first author. It includes all results published earlier and in this paper, ordered alphabetically by chemical. A SAS database is also available.
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The causes and prevention of cancer: the role of environment.
The idea that synthetic chemicals such as DDT are major contributors to human cancer has been inspired, in part, by Rachel Carson's passionate book, Silent Spring. This chapter discusses evidence showing why this is not true. We also review research on the causes of cancer, and show why much cancer is preventable. Epidemiological evidence indicates several factors likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors are avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. Already, risks of many forms of cancer can be reduced and the potential for further reductions is great. If lung cancer (which is primarily due to smoking) is excluded, cancer death rates are decreasing in the United States for all other cancers combined. Pollution appears to account for less than 1% of human cancer; yet public concern and resource allocation for chemical pollution are very high, in good part because of the use of animal cancer tests in cancer risk assessment. Animal cancer tests, which are done at the maximum tolerated dose (MTD), are being misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half of the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at these high doses. A plausible explanation for the high frequency of positive results is that testing at the MTD frequently can cause chronic cell killing and consequent cell replacement, a risk factor for cancer that can be limited to high doses. Ignoring this greatly exaggerates risks. Scientists must determine mechanisms of carcinogenesis for each substance and revise acceptable dose levels as understanding advances. The vast bulk of chemicals ingested by humans is natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of these natural pesticides tested at the MTD are rodent carcinogens. Reducing exposure to the 0.01% that are synthetic will not reduce cancer rates. On the contrary, although fruits and vegetables contain a wide variety of naturally-occurring chemicals that are rodent carcinogens, inadequate consumption of fruits and vegetables doubles the human cancer risk for most types of cancer. Making them more expensive by reducing synthetic pesticide use will increase cancer. Humans also ingest large numbers of natural chemicals from cooking food. Over a thousand chemicals have been reported in roasted coffee: more than half of those tested (19/28) are rodent carcinogens. There are more rodent carcinogens in a single cup of coffee than potentially carcinogenic pesticide residues in the average American diet in a year, and there are still a thousand chemicals left to test in roasted coffee. This does not mean that coffee is dangerous but rather that animal cancer tests and worst-case risk assessment, build in enormous safety factors and should not be considered true risks. The reason humans can eat the tremendous variety of natural chemical "rodent carcinogens" is that humans, like other animals, are extremely well protected by many general defense enzymes, most of which are inducible (i.e., whenever a defense enzyme is in use, more of it is made). Since the defense enzymes are equally effective against natural and synthetic chemicals one does not expect, nor does one find, a general difference between synthetic and natural chemicals in ability to cause cancer in high-dose rodent tests. The idea that there is an epidemic of human cancer caused by synthetic industrial chemicals is false. In addition, there is a steady rise in life expectancy in the developed countries. Linear extrapolation from the maximum tolerated dose in rodents to low level exposure in humans has led to grossly exaggerated mortality forecasts. Such extrapo
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The prevention of cancer.
1. The major causes of cancer are as follows: (a) Smoking: about a third of U.S. cancer (90% of lung cancer). (b) Dietary imbalances, e.g., lack of dietary fruits and vegetables: The quarter of the population eating the least fruits and vegetables has double the cancer rate for most types of cancer compared to the quarter eating the most; micronutrients may account for much of the protective effect of fruits and vegetables. Excess calories may also contribute to cancer. (c) Chronic infections: mostly in developing countries. (d) Hormonal factors influenced by life-style. 2. There is no epidemic of cancer, except for lung cancer due to smoking. Cancer mortality rates have declined 16% since 1950 (excluding lung cancer and adjusted for the increased life span of the population). 3. Regulatory policy that is focused on traces of synthetic chemicals is based on misconceptions about animal cancer tests. Recent research contradicts these ideas: (a) Rodent carcinogens are not rare. Half of all chemicals tested in standard high-dose animal cancer tests, whether occurring naturally or produced synthetically, are "carcinogens." (b) There are high-dose effects in these rodent cancer tests that are not relevant to low-dose human exposures and which can explain the high proportion of carcinogens. (c) Though 99.9% of the chemicals humans ingest are natural, the focus of regulatory policy is on synthetic chemicals. Over 1000 chemicals have been described in coffee: 27 have been tested and 19 are rodent carcinogens. Plants that we eat contain thousands of natural pesticides which protect plants from insects and other predators: 64 have been tested and 35 are rodent carcinogens. 4. There is no convincing evidence that synthetic chemical pollutants are important for human cancer. Regulations that try to eliminate minuscule levels of synthetic chemicals are enormously expensive: EPA estimates that total expenditures on environmental regulations cost $140 billion/year. It has been estimated by others that the United States spends 100 times more to prevent one hypothetical, highly uncertain death from a synthetic chemical than it spends to save a life by medical intervention. Attempting to reduce tiny hypothetical risks also has costs; for example, if reducing synthetic pesticides makes fruits and vegetables more expensive, thereby decreasing consumption, then cancer will be increased. 5. Improved health will come from knowledge due to biomedical research and from life-style changes by individuals. Little money is spent on biomedical research or on educating the public about lifestyle hazards, compared to the cost of regulations.
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What do animal cancer tests tell us about human cancer risk?: Overview of analyses of the carcinogenic potency database.
Many important issues in carcinogenesis can be addressed using our Carcinogenic Potency Database, which analyzes and standardizes the literature of chronic carcinogenicity tests in laboratory animals. This review is an update and overview of our analyses during the past 15 years, using the current database that includes results of 5152 experiments on 1298 chemicals. We address the following: 1. More than half the 1298 chemicals tested in long-term experiments have been evaluated as carcinogens. We describe this positivity rate for several subsets of the data (including naturally occurring and synthetic chemicals), and we hypothesize and important role in the interpretation of results for increased cell division due to administration of high doses. 2. Methodological issues in the interpretation of animal cancer tests: constraints on the estimation of carcinogenic potency and validity problems associated with using the limited data from bioassays to estimate human risk, reproducibility of results in carcinogenesis bioassays, comparison of lifetable and summary methods of analysis, and summarizing carcinogenic potency when multiple experiments on a chemical are positive. 3. Positivity is compared in bioassays for two closely related species, rats and mice, tested under similar experimental conditions. We assess what information such a comparison can provide about interspecies extrapolation. 4. Rodent carcinogens induce tumors in 35 different target organs. We describe the frequency of chemicals that induce tumors in rats or mice at each target site, and we compare target sites of mutagenic and nonmutagenic rodent carcinogens. 5. A broad perspective on evaluation of possible cancer hazards from rodent carcinogens is given, by ranking 74 human exposures (natural and synthetic) on the HERP indes.
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Trichloroethylene cancer risk: simplified calculation of PBPK-based MCLs for cytotoxic end points.
Cancer risk assessments for trichloroethylene (TCE) based on linear extrapolation from bioassay results are questionable in light of new data on TCE's likely mechanism of action involving induced cytotoxicity, for which a threshold-type dose-response model may be more appropriate. Previous studies have shown that if a genotoxic mechanism for TCE is assumed, algebraic methods can considerably simplify the use of physiologically based pharmacokinetic (PBPK) models to estimate virtually safe environmental concentrations for humans based on rodent cancer-bioassay data. We show here how such methods can be extended to the case in which TCE is assumed to induce cancer via cytotoxicity, to estimate environmentally safe concentrations based on rodent toxicity data. These methods can be substituted for the numerical methods typically used to calculate PBPK-effective doses when these are defined as peak concentrations. We selected liver and kidney as plausible target tissues, based on an analysis of rodent TCE-bioassay data and on a review of related data bearing on mechanism. Tumor patterns in rodent bioassays are shown to be consistent with our estimates of PBPK-based, effective cytotoxic doses to mice and rats used in these studies. When used with a margin of exposure of 1000, our method yielded maximum concentration levels for TCE of 16 ppb (87 micrograms/m3) for TCE in air respired 24 hr/day, 700 ppb (3.8 mg/m3) for TCE in air respired for relatively brief daily periods (e.g., 0.5 hr while showering/bathing), and 210 micrograms/liter for TCE in drinking water assuming a daily 2-liter ingestion. Cytotoxic effective doses were also estimated for occupational respiratory exposures. These estimates indicate that the current OSHA permissible exposure limit for TCE would produce metabolite concentrations that exceed an acute no observed adverse effect level for hepatotoxicity in mice. On this basis, the OSHA TCE limit is not expected to be protective.
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Environmental pollution, pesticides, and the prevention of cancer: misconceptions.
The major causes of cancer are: 1) smoking, which accounts for about a third of U.S. cancer and 90% of lung cancer; 2) dietary imbalances: lack of sufficient amounts of dietary fruits and vegetables. The quarter of the population eating the fewest fruits and vegetables has double the cancer rate for most types of cancer than the quarter eating the most; 3) chronic infections, mostly in developing countries; and 4) hormonal factors, influenced primarily by lifestyle. There is no cancer epidemic except for cancer of the lung due to smoking. Cancer mortality rates have declined by 16% since 1950 (excluding lung cancer). Regulatory policy that focuses on traces of synthetic chemicals is based on misconceptions about animal cancer tests. Recent research indicates that rodent carcinogens are not rare. Half of all chemicals tested in standard high-dose animal cancer tests, whether occurring naturally or produced synthetically, are "carcinogens"; there are high-dose effects in rodent cancer tests that are not relevant to low-dose human exposures and which contribute to the high proportion of chemicals that test positive. The focus of regulatory policy is on synthetic chemicals, although 99.9% of the chemicals humans ingest are natural. More than 1000 chemicals have been described in coffee: 28 have been tested and 19 are rodent carcinogens. Plants in the human diet contain thousands of natural "pesticides" produced by plants to protect themselves from insects and other predators: 63 have been tested and 35 are rodent carcinogens. There is no convincing evidence that synthetic chemical pollutants are important as a cause of human cancer. Regulations targeted to eliminate minuscule levels of synthetic chemicals are enormously expensive: the Environmental Protection Agency has estimated that environmental regulations cost society $140 billion/year. Others have estimated that the median toxic control program costs 146 times more per hypothetical life-year saved than the median medical intervention. Attempting to reduce tiny hypothetical risks has other costs as well: if reducing synthetic pesticides makes fruits and vegetables more expensive, thereby decreasing consumption, then the cancer rate will increase, especially for the poor. The prevention of cancer will come from knowledge obtained from biomedical research, education of the public, and lifestyle changes made by individuals. A reexamination of priorities in cancer prevention, both public and private, seems called for.
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The causes and prevention of cancer: gaining perspective.
Epidemiological studies have identified several factors that are likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors include avoidance of intense sun exposure, increased physical activity, and reduced consumption of alcohol and possibly red meat. Risks of many types of cancer can already be reduced, and the potential for further reductions is great. In the United States, cancer death rates for all cancers combined are decreasing, if lung cancer (90% of which is due to smoking), is excluded from the analysis. We review the research on causes of cancer and show why much cancer is preventable. The idea that traces of synthetic chemicals, such as DDT, are major contributors to human cancer is not supported by the evidence, yet public concern and resource allocation for reduction of chemical pollution are very high, in part because standard risk assessment uses linear extrapolation from limited data in high-dose animal cancer tests. These tests are done at the maximum tolerated dose (MTD) and are typically misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at such high doses. Almost all chemicals in the human diet are natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of the natural pesticides that have been tested at the MTD are rodent carcinogens. Cooking food produces large numbers of natural dietary chemicals. Roasted coffee, for example, contains more than 1000 chemicals: of 27 tested, 19 are rodent carcinogens. Increasing evidence supports the idea that the high frequency of positive results in rodent bioassays is due to testing at the MTD, which frequently can cause chronic cell killing and consequent cell replacement-a risk factor for cancer that can be limited to high doses. Because default risk assessments use linear extrapolation, which ignores effects of the high dose itself, low-dose risks are often exaggerated.
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Re: E. Farber, Cell proliferation as a major risk factor for cancer: a concept of doubtful validity. Cancer Res., 55: 3759-3762, 1995.
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Concordance between rats and mice in bioassays for carcinogenesis.
According to current policy, chemicals are evaluated for possible cancer risk to humans at low dose by testing in bioassays in which high doses of the chemical are given to rodents. Thus, risk is extrapolated from high dose in rodents to low dose in humans. The accuracy of these extrapolations is generally unverifiable because data on humans are limited. However, it is feasible to examine the accuracy of extrapolations from mice to rats. If mice and rats are similar with respect to carcinogenesis, this provides some evidence in favor of interspecies extrapolations; conversely, if mice and rats are different, this casts doubt on the validity of extrapolations from mice to humans. One measure of interspecies agreement is concordance, the percentage of chemicals that are classified the same way as to carcinogenicity in mice and rats. Observed concordance in National Cancer Institute/National Toxicology Program bioassays is about 75%, which may seem on the low side because mice and rats are closely related species tested under the same experimental conditions. However, observed concordance could underestimate true concordance due to measurement error in the bioassays-a possibility demonstrated by Piegorsch et al. (Risk Anal. 12, 115-121, 1992). Expanding on this work, we show that the bias in observed concordance can be either positive or negative: an observed concordance of 75% can arise if the true concordance is anything between 20 and 100%. In particular, observed concordance can seriously overestimate true concordance.
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Cancer prevention, rodent high-dose cancer tests, and risk assessment.
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Animals↗
The causes and prevention of cancer.
Epidemiological evidence indicates that avoidance of smoking, increased consumption of fruits and vegetables, and control of infections will have a major effect on reducing rates of cancer. Other factors include avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. A substantial reduction in breast cancer is likely to require modification of sex hormone levels, and development of practical methods for doing so is a high research priority. Resolution of the potential protective roles of specific antioxidants and other constituents of fruits and vegetables deserves major attention. Mechanistic studies of carcinogenesis indicate an important role of endogenous oxidative damage to DNA that is balanced by elaborate defense and repair processes. Also key is the rate of cell division, which is influenced by hormones, growth, cytotoxicity, and inflammation, as this determines the probability of converting DNA lesions to mutations. These mechanisms may underlie many epidemiologic observations.
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Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays.
With a limited subset of National Cancer Institute/National Toxicology Program (NCI/NTP) bioassays, Gaylor (Regul. Toxicol. Pharmacol. 9, 101-108, 1989) showed that the regulatory virtually safe dose (VSD), corresponding to an estimated lifetime cancer risk of less than 10(-6), could be estimated within a factor of 10 simply by dividing the maximum tolerated dose (MTD), estimated from the results of a 90-day study, by 380,000. The purpose of this current study was to extend the analysis to all carcinogens in the Carcinogenic Potency Database (CPDB) utilizing the TD50 (average daily dose rate in mg/kg body wt/day that was estimated to halve the probability of remaining tumor-free at a specified tissue site throughout a 2-year study). Using the relationship between the upper bound on the low-dose slope (q1*) and the TD50 reported by Krewski et al. (Risk Anal. 13, 383-398, 1993) and the ratio of the maximum dose tested (Max-D)/TD50 obtained in our present analysis, an estimate of the regulatory VSD was given by the MTD/740,000, for NCI/NTP rodent carcinogens. This was about a factor of two lower than the limited analysis conducted by Gaylor. There was little difference when the chemicals were divided into mutagens and nonmutagens. Ninety-six percent (134 of the 139 NCI/NTP rodent carcinogens) of the regulatory VSDs calculated from the individual TD50s obtained from the 2-year bioassays were within a factor of 10 of the MTD/740,000.(ABSTRACT TRUNCATED AT 250 WORDS)
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Sixth plot of the carcinogenic potency database: results of animal bioassays published in the General Literature 1989 to 1990 and by the National Toxicology Program 1990 to 1993.
This paper presents two types of information from the Carcinogenic Potency Database (CPDB): (a) the sixth chronological plot of analyses of long-term carcinogenesis bioassays, and (b) an index to chemicals in all six plots, including a summary compendium of positivity and potency for each chemical (Appendix 14). The five earlier plots of the CPDB have appeared in this journal, beginning in 1984 (1-5). Including the plot in this paper, the CPDB reports results of 5002 experiments on 1230 chemicals. This paper includes bioassay results published in the general literature between January 1989 and December 1990, and in Technical Reports of the National Toxicology Program between January 1990 and June 1993. Analyses are included on 17 chemicals tested in nonhuman primates by the Laboratory of Chemical Pharmacology, National Cancer Institute. This plot presents results of 531 long-term, chronic experiments of 182 test compounds and includes the same information about each experiment in the same plot format as the earlier papers: the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications (1,6,7) for a detailed guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The six plots of the CPDB are to be used together since results of individual experiments that were published earlier are not repeated. Appendix 14 is designed to facilitate access to results on all chemicals. References to the published papers that are the source of experimental data are reported in each of the published plots. For readers using the CPDB extensively, a combined plot is available of all results from the six separate plot papers, ordered alphabetically by chemical; the combined plot in printed form or on computer tape or diskette is available from the first author. A SAS database is also available.
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Heterocyclic amines formed by cooking food: comparison of bioassay results with other chemicals in the Carcinogenic Potency Database.
Results in the Carcinogenic Potency Database (CPDB) on 11 mutagenic heterocyclic amines (HA) tested for carcinogenicity in rats, mice and cynomolgus monkeys are compared to results for other chemicals. An analysis of strength of evidence of carcinogenicity for HA vs. other mutagenic carcinogens and vs. all rodent carcinogens, indicates strong carcinogenicity of HA in terms of positivity rates and multiplicity of target sites. The liver is the most frequent target site in each species. Despite several target sites in each species, concordance in target sites between rats and mice is restricted to the liver for each HA except one. In cynomolgus monkeys, liver tumors have been induced rapidly by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Human exposures to HA in cooked animal foods are small, in the low ppb range. A comparison of possible carcinogenic hazards from a variety of exposures to rodent carcinogens in the American diet is presented, using an index (Human Exposure/Rodent Potency, HERP) that relates human exposure to carcinogenic potency in rodents. Results indicate that there is a large background of exposures to naturally-occurring rodent carcinogens in typical portions of common foods, and that possible hazards from HA rank below those of most natural pesticides and products of cooking or food preparation; synthetic pesticide residues also rank low.
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Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals.
A comparison of target organs for mutagens and non-mutagens is presented for 351 rodent carcinogens in the Carcinogenic Potency Database (CPDB) with mutagenicity evaluations in Salmonella. Results are consistent with the hypotheses that in high-dose rodent tests mitogenesis is important in the carcinogenic response for mutagens and non-mutagens alike, and that mutagens have a multiplicative interaction for carcinogenicity because they can both damage DNA directly and cause cell division at high doses. These hypotheses would lead one to expect several results that are found in the analysis: First, a high proportion of both mutagens and non-mutagens induce tumors in rodent bioassays at the MTD. Second, mutagens compared to non-mutagens are: (a) more likely to be carcinogenic; (b) more likely to induce tumors at multiple target sites; and (c) more likely to be carcinogenic in two species. Among carcinogens that induce tumors at multiple sites in both rats and mice, 81% are mutagens; in comparison, among carcinogens that are positive at only a single target site in one species and are negative in the other, 42% are mutagens. Since tissue distribution and pharmacokinetics would not be expected to differ systematically between mutagens and non-mutagens, one would not expect systematic differences in the particular organs in which tumors are induced. Results do not support the idea that mutagens and non-mutagens induce tumors in different target organs. Both mutagens and non-mutagens induce tumors in a wide variety of sites, and most organs are target sites for both. Moreover, the same sites tend to be the most common sites for both: 79% or more of both mutagenic and non-mutagenic carcinogens are positive in each species in at least one of the 8 most frequent target sites: liver, lung, mammary gland, stomach, vascular system, kidney, hematopoietic system and urinary bladder. Species differences are discussed as well as results for particular target organs: liver, Zymbal's gland and kidney.
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Prediction of carcinogenicity from two versus four sex-species groups in the carcinogenic potency database.
Prediction of a positive result in rodent carcinogenesis bioassays using two instead of four sex-species groups is examined for the subset of chemicals in the Carcinogenic Potency Database that have been tested in four sex-species groups and are positive in at least one (n = 212). Under the conditions of these bioassays, a very high proportion of rodent carcinogens that are identified as positive by tests in four groups is also identified by results from one sex of each species (86-92%). Additionally, chemicals that are classified as "two-species carcinogens" or "multiple-site carcinogens" on the basis of results from four sex-species groups are also identified as two-species or multiple-site carcinogens on the basis of two sex-species groups. Carcinogenic potency (TD50) values for the most potent target site are similar when based on results from two compared to four sex-species groups. Eighty-five percent of the potency values are within a factor of 2 of those obtained from tests in 4 sex-species groups, 94% are within a factor of 4, and 98% are within a factor of 10. This result is expected because carcinogenic potency values are constrained to a narrow range about the maximum dose tested in a bioassay, and the maximum doses administered to rats and mice are highly correlated and similar in dose level. Information that can be known in advance of a 2-yr bioassay (mutagenicity, class, route, and maximum dose to test) does not identify groups of rodent carcinogens for which four sex-species groups are required to identify carcinogenicity. The range of accurate prediction of carcinogenicity using only male rats and female mice is 93% among mutagens and 88% among nonmutagens; for various routes of administration, 88-100%; for various chemical classes, 75-100%; and for various levels of the maximum dose tested, 81-100%. Results are similar for the pair male rats and male mice. Using a strength of evidence approach, weaker carcinogens are somewhat less likely than stronger carcinogens to be identified by two sex-species groups. Strength of evidence is measured using the proportion of experiments on a chemical that are positive, the extent to which tumors occur in animals that die before terminal sacrifice, and whether the chemical induces tumors at more than one site and in more than one species.
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