National Cancer Institute/National Toxicology Program Research Articles

Supplement to the Carcinogenic Potency Database (CPDB): Results of Animal Bioassays Published in the General Literature through 1997 and by the National Toxicology Program in 1997–1998

The Carcinogenic Potency Database (CPDB) is a systematic and unifying resource that standardizes the results of chronic, long-term animal cancer tests which have been conducted since the 1950s. The analyses include sufficient information on each experiment to permit research into many areas of carcinogenesis. Both qualitative and quantitative information is reported on positive and negative experiments that meet a set of inclusion criteria. A measure of carcinogenic potency, TD(50) (daily dose rate in mg/kg body weight/day to induce tumors in half of test animals that would have remained tumor-free at zero dose), is estimated for each tissue-tumor combination reported. This article is the ninth publication of a chronological plot of the CPDB; it presents results on 560 experiments of 188 chemicals in mice, rats, and hamsters from 185 publications in the general literature updated through 1997, and from 15 Reports of the National Toxicology Program in 1997-1998. The test agents cover a wide variety of uses and chemical classes. The CPDB Web Site (http://potency.berkeley.edu/) presents the combined database of all published plots in a variety of formats as well as summary tables by chemical and by target organ, supplemental materials on dosing and survival, a detailed guide to using the plot formats, and documentation of methods and publications. The overall CPDB, including the results in this article, presents easily accessible results of 6153 experiments on 1485 chemicals from 1426 papers and 429 NCI/NTP (National Cancer Institute/National Toxicology program) Technical Reports. A tab-separated format of the full CPDB for reading the data into spreadsheets or database applications is available on the Web Site.

T25: a simplified carcinogenic potency index: description of the system and study of correlations between carcinogenic potency and species/site specificity and mutagenicity.

A simplified carcinogenic potency index, the T25, is proposed as a practical method for the inclusion of potency considerations in carcinogen classification systems. The T25 is the chronic daily dose in mg per kg bodyweight which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard life span of that species. Calculated T25 values of a set of 113 US National Cancer Institute/National Toxicology Program (NC/NTP) carcinogens showed excellent correlation (correlation coefficient 0.96, P < 0.0001) with the carcinogenic potency index TD50 of Peto et al. (1984). The mean of T25 values for 51 transspecies, multiple common site NCI/NTP carcinogens were 10-fold lower than those for 62 NCI/NTP single species, single site carcinogens. For these 113 carcinogens, the mean T25 values were approximately 3-fold lower for agents that were also mutagenic in Salmonella compared to the non-mutagenic agents.

Assessment of effect levels of chemicals from quantitative structure-activity relationship (QSAR) models. I. Chronic lowest-observed-adverse-effect level (LOAEL)

With the multitude of new chemicals being synthesized and the paucity of long-term test data on chemicals that could be introduced into the environment, innovative approaches must be developed to determine the health and environmental effects of chemicals. Research was conducted to employ quantitative structure-activity relationship (QSAR) techniques to study the feasibility of developing models to estimate the noncarcinogenic toxicity of chemicals that are not addressed in the literature by relevant studies. A database of lowest-observed-adverse-effect level (LOAEL) was assembled by extracting toxicity information from 104 U.S. EPA documents, 124 National Cancer Institute/National Toxicology Program (NCI/NTP) reports, and 6 current reports from the literature. A regression model, based on 234 chemicals of diverse structures and chemical classes including both alicyclic and aromatic compounds, was developed to assess the chronic oral LOAELs in rats. The model was incorporated into an automated computer package. Initial testing of this model indicates it has application to a wide range of chemicals. For about 55% of the compounds in the data set, the estimated LOAELs are within a factor of 2 of the observed LOAELs. For over 93%, they are within a factor of 5. Because of the paucity or absence of long-term toxicity data, the public health and risk assessment community could utilize such QSAR models to determine initial estimates of toxicity for the ever-increasing numbers of chemicals that lack complete pertinent data. However, this and other such models should be used only by expert toxicologists who must objectively look at the estimates thus generated in light of the overall weight of evidence of the available toxicologic information of the subject chemical(s).

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 a-year study). Using the relationship between the upper bound on the low-dose slope (q*1) 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. Gold et al. (Environ. Health Perspect. 79, 259-272, 1989) investigated the distribution of the TD50 among "near-replicate" experiments (where the same chemical was tested more than once and was positive in the same strain, sex, and species by the same route). The distribution of TD50s from near-replicate experiments is similar to the distribution of the Max-D/TD50. Hence, the estimate of the regulatory VSD based on the Max-D/740,000, for NCI/NTP bioassays, is about as precise as the estimate obtained from a 2-year bioassay. This questions the advisability of conducting a 2-year bioassay for purposes of regulatory risk estimation. Since resources are available to test only a small fraction of chemicals to which humans are exposed, a preliminary estimate of the regulatory VSD can be useful in setting testing priorities. If the expected human exposure level is below the regulatory VSD estimated from the MTD, a chemical may be assigned low priority for testing in a 2-year bioassay. Based on previous work the FDA proposed a "threshold of regulation" of a dietary concentration of 0.5 ppb for all substances used in food-contact articles. The results of the present analysis could be used to make the procedure more chemical specific based upon an available MTD. The high correlation between the MTD and estimate of cancer potency (TD50) can be exploited to provide a preliminary, hypothetical upper bound estimate of cancer risk for exposure to a chemical without conducting a 2-year animal bioassay. Thus, the expected level of human exposure relative to the MTD can be used to determine the priority for further research on a chemical, such as mechanistic studies.

The carcinogenesis bioassay in perspective: application in identifying human cancer hazards.

The selection process for chemicals tested in the rodent carcinogenicity bioassay has been biased toward chemicals suspected of potential carcinogenicity. Results from carcinogenicity bioassays of 400 chemicals tested by the National Cancer Institute/National Toxicology Program (NCI/NTP) were analyzed to determine the dependence of positive results on chemical selection criteria: those suspected of being carcinogenic and those selected based on large volumes produced and widespread exposures. Of these chemicals, 210 (52%) induced carcinogenicity in at least one organ of one sex of one species of the four sex/species groups typically used by NCI/NTP. Only 92 of the 400 chemicals (23%) were positive in two species and thus by international criteria are considered likely to pose a carcinogenic hazard to humans. A total of 267 chemicals (67%) were selected as suspect carcinogens, and 187 (68%) of these were carcinogenic. Suspect chemicals account for 86% of chemicals with at least one positive result and account for 90% of chemicals considered positive in two species. The International Agency for Research on Cancer (IARC) lists only 5 of the 400 chemicals as carcinogenic to humans (group 1) and 10 as probably carcinogenic to humans (group 2A). The majority (80%) of the 133 chemicals selected only on production/exposure considerations were not carcinogenic in animals, even when tested at the maximum tolerated (or minimally toxic) dose. Only 9 (6.8%) were positive in two species, and none is listed in IARC groups 1 or 2A. Thus, on the basis of our analyses we predict that less than 5-10% of the 75,000 chemicals in commercial use might be reasonably anticipated to be carcinogenic to humans.

Nonlinearity of dose-response functions for carcinogenicity.

Carcinogenesis data for 315 chemicals were obtained from the National Cancer Institute-National Toxicology Program (NCI-NTP) bioassay programs and were analyzed to examine the shape of carcinogenesis dose-response curves. Tumor site data were more often consistent with a quadratic response than with a linear response, suggesting that the routine use of linear dose-response models will often overestimate risk. Information from in vivo short-term mutagenicity and genotoxicity assays was also obtained for most of these rodent bioassays. It was found that there were no clear relationships between the shape of the carcinogenesis dose-response curve and the result of the short-term test. These observations argue against the concept that carcinogens that are positive in a short-term assay be regulated using a linear dose-response curve and those that are negative be regulated using a sublinear dose-response curve or a safety factor approach.

Predictive Strategies for Selecting 379 NCI/NTP Chemicals Evaluated for Carcinogenic Potential: Scientific and Public Health Impact

Predictive Strategies for Selecting 379 NCI/NTP Chemicals Evaluated for Carcinogenic Potential: Scientific and Public Health Impact. Fung, V. A., Huff, J. H., Weisburger, E. K., and Hoel, D. G. (1993). Fundam. Appl. Toxicol. 20, 413-436.The a priori criteria used by the National Cancer Institute/National Toxicology Program (NCI/NTP) are described for 379 chemicals selected and evaluated for carcinogenic potential. We classified the chemicals according to exposure and structural categories and evaluated the predictive ability of the scientific selection criteria of chemicals suspected of being carcinogenic in advance of any study. Of the 379 chemicals, 253 (67%) were selected with a suspicion of carcinogenicity; 171 (68%) of these 253 chemicals induced cancer in at least one of the sex-species experiments. The other 126 (33%) chemicals were selected mainly, but not exclusively, on the basis of exposure considerations and production volumes; only 27 (21%) of these were judged to be positive. Overall, 198 (52%) of the 379 chemicals studied induced tumors in at least one organ of one sex of one species, but only 87 (23%) of these 379 chemicals were positive in both species and are considered most likely to present carcinogenic hazards to humans. Importantly, 78 (90%) of these 87 chemicals were selected with a prospective suspicion of carcinogenicity. Although the program has studied only a part of the "Universe of Chemicals" (defined as chemicals to which humans are exposed), the scientific data generated are essential for developing structure activity data bases of potentially hazardous chemical classes and for predicting the carcinogenicity of chemicals not yet studied. Thus, the bioassay program has had beneficial and crucial impacts on public health, as demonstrated by the use of these data by international, Federal, and State regulatory agencies to reduce or eliminate exposures to chemicals shown to be unequivocally carcinogenic in laboratory animals.

Predictive Strategies for Selecting 379 NCI/NTP Chemicals Evaluated for Carcinogenic Potential: Scientific and Public Health Impact

The a priori criteria used by the National Cancer Institute/National Toxicology Program (NCI/NTP) are described for 379 chemicals selected and evaluated for carcinogenic potential. We classified the chemicals according to exposure and structural categories and evaluated the predictive ability of the scientific selection criteria of chemicals suspected of being carcinogenic in advance of any study. Of the 379 chemicals, 253 (67%) were selected with a suspicion of carcinogenicity; 171 (68%) of these 253 chemicals induced cancer in at least one of the sex-species experiments. The other 126 (33%) chemicals were selected mainly, but not exclusively, on the basis of exposure considerations and production volumes; only 27 (21%) of these were judged to be positive. Overall, 198 (52%) of the 379 chemicals studied induced tumors in at least one organ of one sex of one species, but only 87 (23%) of these 379 chemicals were positive in both species and are considered most likely to present carcinogenic hazards to humans. Importantly, 78 (90%) of these 87 chemicals were selected with a prospective suspicion of carcinogenicity. Although the program has studied only a part of the “Universe of Chemicals“ (defined as chemicals to which humans are exposed), the scientific data generated are essential for developing structure activity data bases of potentially hazardous chemical classes and for predicting the carcinogenicity of chemicals not yet studied. Thus, the bioassay program has had beneficial and crucial impacts on public health, as demonstrated by the use of these data by international, Federal, and State regulatory agencies to reduce or eliminate exposures to chemicals shown to be unequivocally carcinogenic in laboratory animals.

Estimation of Maximum Tolerated Dose for Long‐Term Bioassays from Acute Lethal Dose and Structure by QSAR

A quantitative structure-activity relationship (QSAR) model has been developed to estimate maximum tolerated doses (MTD) from structural features of chemicals and the corresponding oral acute lethal doses (LD50) as determined in male rats. The model is based on a set of 269 diverse chemicals which have been tested under the National Cancer Institute/National Toxicology Program (NCI/NTP) protocols. The rat oral LD50 value was the strongest predictor. Additionally, 22 structural descriptors comprising nine substructural MOLSTAC(c) keys, three molecular connectivity indices, and sigma charges on 10 molecular fragments were identified as endpoint predictors. The model explains 76% of the variance and is significant (F = 35.7) at p less than 0.0001 with a standard error of the estimate of 0.40 in the log (1/mol) units used in Hansch-type equations. Cross-validation showed that the difference between the average deleted residual square (0.179) and the model residual square (0.160) was not significant (t = 0.98).

Federal regulation of carcinogens lagging

Chemicals identified as cancercausing are not being systematically regulated by the federal agencies charged with protecting the public from chemical hazards, according to the Congressional Office of Technology Assessment. Fewer than half the 145 chemicals listed in the federal government's Annual Report on Carcinogens have been regulated, notes a just-released OTA report, Identifying and Regulating Carcinogens. And agencies have regulated fewer than one third of the chemicals testing positive for carcinogenicity under the animal test program of the National Cancer Institute /National Toxicology Program (NCI/NTP). Of more than 300 chemicals tested in that program, 144 show some evidence of carcinogenicity. The Food & Drug Administration, for instance, has acted on just 17 of 48 positive-testing chemicals associated with food or color additives or cosmetics. The Occupational Safety & Health Administration has set exposure standards for 29 of 53 positive-testing chemicals found in the workplace, but 27 of...

Carcinogenic Risk Assessment: Comparison of Estimated Safe Doses for Rats and Mice

Data from the National Cancer Institute/National Toxicology Program (NCI/NTP) carcinogenesis bioassays were examined to compare cancer risks in rats and mice. Only those bioassays where chemicals were administered orally were used. The ratios for rats to mice of the virtually safe dose (VSD) levels associated with a risk of 10(-6) were compared. Comparisons of the ratios were made for those chemicals that NCI/NTP determined to be carcinogenic in at least one species and that showed a dose response trend in the same sex at the same tissue/organ site in the other species. In all, 69 comparisons from 38 carcinogens were performed. The overall geometric mean of the VSD ratios is 1.27 in terms of concentration (ppm); the mean and the standard deviation in logarithm are 0.24 and 1.83, respectively. The VSD ratios vary from 1:51 to 49:1. Without the restriction of the same sex and site, the geometric mean of the minimum VSDs is 1.38, and the standard deviation in logarithm is 1.79. By directly comparing the VSDs for rats and mice (as they are performed for risk assessment), this study showed a probability of 0.10 that the ratio of VSDs is greater than 10, and the ratio is greater than 20 with a probability of 0.05 when a chemical is carcinogenic in both species.

Lung neoplasms in rodents after chronic administration of dimethyl hydrogen phosphite

Dimethyl hydrogen phosphite (DMHP), an intermediate in the production of insecticides or herbicides, was administered by p.o. gavage for 2 yr to male Fischer 344/N rats and male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to female Fischer 344/N rats at doses of 0, 50 or 100 mg/kg. Dose related toxicity was seen in the lungs of treated male and female rats. The lung lesions were most prevalent in the high dose male rat group which received a dose twice that given to the high dose female rats. Lung lesions included alveolar epithelial hyperplasia, chemically related pneumonia, alveolar-bronchiolar adenoma, alveolar-bronchiolar carcinoma, and squamous cell carcinoma. DMHP also caused neoplastic and nonneoplastic lesions of the forestomach in male rats; a similar but less pronounced effect was observed in female rats. Nonneoplastic lesions associated with administration of DMHP included mineralization of the cerebellum in male rat and focal calcification of the testis in male mice. Under the conditions of this study, there was clear evidence for carcinogenicity for male rats, equivocal evidence for carcinogenicity in female rats, and no evidence for carcinogenicity in either male or female mice. DMHP caused the highest incidence of lung tumors in the male rat of all chemicals studied to date in the National Cancer Institute-National Toxicology Program Carcinogenesis Testing Program.

A reexamination of false-positive rates for carcinogenesis studies

False-positive rates in the National Cancer Institute/National Toxicology Program (NCI/NTP) two-year carcinogenesis bioassay are examined. Previous studies that have reported high (20–50%) false-positive rates for these bioassays are reviewed. The decision rules used in many of these earlier investigations are far different than the procedures actually employed by the NCI/NTP in the interpretation of bioassay data. Data from 25 recent NTP feeding studies are examined, and the statistical significance of observed tumor increases are compared with the final interpretations regarding the carcinogenic effects of the chemicals under study. Based on this examination, a more realistic decision procedure is formulated. It is shown that under the assumption of a statistical decision rule which appears to mimic more closely the scientific judgment process, the actual overall false-positive rate in NCI/NTP bioassays appears to be no greater than 7% to 8%.

A Reexamination of False-Positive Rates for Carcinogenesis Studies

A Reexamination of False-positive Rates for Carcinogenesis Studies. Haseman, J.K. (1983). Fundant. Appl. Toxicol. 3:334-339. False-positive rates in the National Cancer Institute/National Toxicology Program (NCI/NTP) two-year carcinogenesis bioassay are examined. Previous studies that have reported high (20-50%) false-positive rates for these bioassays are reviewed. The decision rules used in many of these earlier investigations are far different than the procedures actually employed by the NCI/NTP in the interpretation of bioassay data. Data from 25 recent NTP feeding studies are examined, and the statistical significance of observed tumor increases are compared with the final interpretations regarding the carcinogenic effects of the chemicals under study. Based on this examination, a more realistic decision procedure is formulated. It is shown that under the assumption of a statistical decision rule which appears to mimic more closely the scientific judgment process, the actual overall false-positive rate in NCI/NTP bioassays appears to be no greater than 7% to 8%.