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L S Gold

Publications and source records attributed to L S Gold.

At least 55 records · Page 3Linked to original sources
PubMed1990

Third chronological supplement to the carcinogenic potency database: standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987.

This paper is the third chronological supplement to the Carcinogenic Potency Database that first appeared in this journal in 1984. We report here results of carcinogenesis bioassays published in the general literature between January 1985 and December 1986, and in Technical Reports of the National Toxicology Program between June 1986 and June 1987. This supplement includes results of 337 long-term, chronic experiments of 121 compounds, and reports the same information about each experiment in the same plot format as the earlier papers, e.g., the species and strain of 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, opinion of the author about carcinogenicity, and literature citation. The reader needs to refer to the 1984 publication for a 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 four plots of the database are to be used together as results published earlier are not repeated. In all, the four plots include results for approximately 4000 experiments on 1050 chemicals. Appendix 14 of this paper is an alphabetical index to all chemicals in the database and indicates which plot(s) each chemical appears in. A combined plot of all results from the four separate papers, that is ordered alphabetically by chemical, is available from the first author, in printed form or on computer tape or diskette.

Carcinogenicity Tests↗
PubMed1990

Natural chemicals, synthetic chemicals, risk assessment, and cancer.

The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis), which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism, because a high proportion--about half--of all chemicals tested (whether natural or synthetic) are indeed rodent carcinogens. We conclude that at the low doses of most human exposures, where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed. The toxicological significance of exposures to synthetic chemicals is examined in the context of exposures to naturally occurring chemicals. We calculate that 99.99% (by weight) of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. The toxicology of synthetic chemicals is compared to that of natural chemicals, which represent the vast bulk of the chemicals to which humans are exposed. It is argued that animals have a broad array of inducible general defenses to combat the changing array of toxic chemicals in plant food (nature's pesticides) and that these defenses are effective against both natural and synthetic toxins. Synthetic toxins such as dioxin are compared to natural chemicals, such as indole carbinol (in broccoli) and ethanol. The finding that in high-dose tests, a high proportion of both natural and synthetic chemicals are carcinogens, mutagens, teratogens, and clastogens (30-50% for each group) undermines current regulatory effects based on these tests to protect public health from low doses of synthetic chemicals.

Antioxidants↗
PubMed1989

Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database.

A tabulation of carcinogenic potency (TD50) by species for 492 chemicals that induce tumors in rats or mice is presented. With the use of the Carcinogenic Potency Database, experimental results are summarized by indicating in which sex-species groups the chemical was tested and the respective evaluations of carcinogenicity. A comparison of three summary measures of TD50 for chemicals with more than one positive experiment per species shows that the most potent TD50 value is similar to measures that average values or functions of values. This tabulation can be used to investigate associations between rodent potency and other factors such as mutagenicity, teratogenicity, chemical structure, and human exposure.

Animals↗
PubMed1989

Interspecies extrapolation in carcinogenesis: prediction between rats and mice.

Interspecies extrapolation in carcinogenesis is studied by evaluating prediction from rats to mice and from mice to rats. The Carcinogenic Potency Database, which includes 3500 cancer tests conducted in rats or mice on 955 compounds, is used for the analysis. About half of the chemicals tested for carcinogenicity are positive in at least one test, and this proportion is similar when rats and mice are considered separately. For 392 chemicals tested in both species, 76% of the rat carcinogens are positive in the mouse, and 70% of mouse carcinogens are positive in the rat. When compounds composed solely of chlorine, carbon, hydrogen, and, optionally, oxygen are excluded from the analysis, 75% of mouse carcinogens are positive in the rat. Overall concordance (the percentage positive in both species plus the percentage negative in both) is 76%. Three factors that affect prediction between rats and mice are discussed: chemical class, mutagenicity in the Salmonella assay, and the dose level at which a chemical is toxic. Prediction is more accurate for mutagens than non-mutagens and for substances that are toxic at low (versus only at high) doses. Species differences are not the result of failure in the bioassay to attain the maximum tolerated dose in the negative species or of more frequent testing in the positive species. An analysis of the predictive value of positivity for the 10 most common target sites indicates that most sites are good predictors of carcinogenicity at some site in the other species; the poorest predictors among these common sites are the rat urinary bladder and the mouse liver.

Animals↗
PubMed1987

Ranking possible carcinogenic hazards.

This review discusses reasons why animal cancer tests cannot be used to predict absolute human risks. Such tests, however, may be used to indicate that some chemicals might be of greater concern than others. Possible hazards to humans from a variety of rodent carcinogens are ranked by an index that relates the potency of each carcinogen in rodents to the exposure in humans. This ranking suggests that carcinogenic hazards from current levels of pesticide residues or water pollution are likely to be of minimal concern relative to the background levels of natural substances, though one cannot say whether these natural exposures are likely to be of major or minor importance.

Animals↗
PubMed1987

Second chronological supplement to the Carcinogenic Potency Database: standardized results of animal bioassays published through December 1984 and by the National Toxicology Program through May 1986.

This paper is the second chronological supplement to the Carcinogenic Potency Database, published earlier in this journal (1,2,4). We report here results of carcinogenesis bioassays published in the general literature between January 1983 and December 1984, and in Technical Reports of the National Cancer Institute/National Toxicology Program between January 1983 and May 1986. This supplement includes results of 525 long-term, chronic experiments of 199 test compounds, and reports the same information about each experiment in the same plot format as the earlier papers: e.g., 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 for a description of the numerical index of carcinogenic potency (TD50), a guide to the plot of the database, 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 three plots of the database are to be used together, since results of experiments published in earlier plots are not repeated. Taken together, the three plots include results for more than 3500 experiments on 975 chemicals. Appendix 14 is an index to all chemicals in the database and indicates which plot(s) each chemical appears in.

Animals↗
PubMed1987

Ranking the potential carcinogenic hazards to workers from exposures to chemicals that are tumorigenic in rodents.

For 41 chemicals there exist both reasonable data on carcinogenic potency in experimental animals and also a defined Permissible Exposure Level (PEL), which is the upper limit of legally permissible chronic occupational exposure for U.S. workers. These 41 agents are ranked by an index that compares the permitted chronic human exposure to the chronic dose rate that induces tumors in 50% of laboratory animals. This index, the Permitted Exposure/Rodent Potency index, or PERP, does not estimate absolute risks directly, but rather suggests the relative hazards that such substances may pose. The PERP values for these 41 substances differ by more than 100,000-fold from each other. The PERP does not take into account the actual level of exposure or the number of exposed workers. Nevertheless, it might be reasonable to give priority attention to the reduction of allowable worker exposures to substances that appear most hazardous by this index and that some workers may be exposed to full-time near the PEL. Ranked by PERP, these chemicals are: ethylene dibromide, ethylene dichloride, 1,3-butadiene, tetrachloroethylene, propylene oxide, chloroform, formaldehyde, methylene chloride, dioxane, and benzene.

Animals↗
PubMed1987

Reproducibility of results in "near-replicate" carcinogenesis bioassays.

Reproducibility of results was examined in 70 "near-replicate" comparisons consisting of 2 or more long-term carcinogenesis bioassays of the same chemical administered by the same route and using the same sex and strain of rodent. Overall, there was good reproducibility of positivity, target site, and carcinogenic potency in hamsters, mice, and rats. The published authors' opinions about whether the test was positive disagreed in only 9 of the 70 comparisons. Among the 35 comparisons in which all tests of the chemical were positive, 33 of the near-replicates had at least 1 identical target site. The carcinogenic potency values estimated from near-replicate tests in these 35 comparisons were within a factor of 2 of each other in 40% of the comparisons, within a factor of 5 in 80%, and within a factor of 10 in 90%. For the few cases in which the carcinogenic response was not reproduced, analyses suggest two explanations: In mice the discrepant cases tended to have shorter experiment times than average; in both rats and mice the discrepant results tended to be tests of weakly active compounds.

Animals↗
PubMed1986

Association between carcinogenic potency and tumor pathology in rodent carcinogenesis bioassays.

Carcinogenic potency (TD50) estimated from the results of 88 NCI/NTP carcinogenesis bioassays was examined by common target sites in rats and mice. Other indicators of a chemical's hazard were investigated, including whether tumors were induced at more than one site in a single sex-species group of test animals, whether tumors may have caused the death of the animal or were found at sacrifice, and whether metastases of induced tumors occurred. These hazard indicators are sometimes interrelated; however, the potency (TD50) values of chemicals which are hazardous by each of these measures spanned a wide range. Carcinogens which caused some type of fatal tumor were more likely than other carcinogens to cause tumors in multiple organ sites and multiple sex-species groups. Since these other hazard indicators were not related to carcinogenic potency, they should be included along with potency estimates such as the TD50 in summarizing the potential dangers of human exposures to a carcinogen and in comparisons of hazard among carcinogens.

Animals↗
PubMed1986

An empirical comparison of methods used to estimate carcinogenic potency in long-term animal bioassays: lifetable vs summary incidence data.

Two methods for estimating carcinogenic potency from animal carcinogenesis bioassays (TD50-defined in the paper) are compared, one based on lifetable data and one based on summary incidence data. The lifetable analysis adjusts for the differential effects of toxicity among dose groups and for differences in the time pattern of tumor incidence, while summary incidence analysis does not. However, summary data are all that are usually available in the published results of animal cancer tests. Using NCI bioassay results which provide full lifetable data, we compare lifetable and summary estimates of potency and their statistical significance as well as the estimated shape of the dose-response curve. There is substantial agreement between these methods of analysis in terms of potency estimation, although lifetable estimates are usually more potent. But, there are some notable differences in the estimated shape of the dose-response curve, suggesting that both target site selection and method of analysis play an important role in risk estimation.

Actuarial Analysis↗
PubMed1986

Chronological supplement to the Carcinogenic Potency Database: standardized results of animal bioassays published through December 1982.

This paper is a chronological supplement to our earlier publication, "A Carcinogenic Potency Database of the Standardized Results of Animal Bioassays." We report here results of carcinogenesis bioassays published in Technical Reports of the National Cancer Institute/National Toxicology Program between July 1980 and December 1982, and the general literature between July 1981 and December 1982. This supplement includes results of 280 long-term, chronic experiments of 114 test compounds, and reports the same information about each experiment in the same plot format as the earlier paper: e.g., 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 and its statistical significance, dose response, author's opinion about carcinogenicity, and literature reference. While a number of appendices are provided to facilitate use of this supplement, we have not duplicated here the material published earlier. Instead, we refer the reader to the earlier publications (Peto et al. and Gold et al.) for a thorough description of the numerical index of carcinogenic potency (TD50), a guide to the plot of the database, 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. For 44 of the 114 chemicals reported in this second plot, results of earlier experiments are also given in the first plot; since only 1981-1982 results are reported here, the first plot is required for these repeated compounds. In this paper we also give corrections for errors that appeared in the earlier publication.

Animals↗
PubMed1986

Ranking the carcinogenic hazards of occupational exposures: Exposure-Potency Index (EPI) values for nine volatile industrial chemicals.

Employers, employees, and occupational health professionals need a a simple index to rank carcinogens according to their potential danger at exposure levels which are commonly encountered in workplaces. We describe such an index, the Exposure-Potency Index (EPI). This simple proportion, dose level (mg/kg body weight/day) to which workers are permitted to be exposed/cancer-causing dose (mg/kg body weight/day) in test animals, permits comparisons among carcinogens. We have calculated this index for inhalation exposures to 1,3-butadiene, 1,2-dibromo-3-chloropropane (DBCP), 1,2-dibromoethane (EDB), ethylene oxide, formaldehyde, methylene chloride, propylene oxide, tetrachloroethylene (perchloroethylene), and trichloroethylene (TCE). The permitted worker exposure levels have frequently been close to the levels which induce tumors in laboratory animals. More recently, Permissible Exposure Limits (PEL's) for for some chemicals have been markedly reduced, and this is reflected in lowered EPI values. Combining EPI values with information on the numbers of exposed workers provides a simple means of identifying and ranking dangers to populations of workers.

Animals↗
PubMed1985

Some tautologous aspects of the comparison of carcinogenic potency in rats and mice.

In risk estimation, the results of rodent carcinogenesis experiments are often used to quantitatively predict effects in man. The justification for this approach has in large part been dependent upon the good correlation of carcinogenic potency found between mice and rats over large numbers of test chemicals. Using the data base of chemicals tested by the NCI Bioassay Program, we observe that there is a very high correlation of the maximum doses tested (max-d) for rats and mice on a milligram per kilogram body weight per day basis. Next we show that the calculated carcinogenic potency (b-defined in the paper) is restricted to an approximately 30-fold range surrounding log(2)/max-d, which has a biological as well as a statistical basis. Since the max-d's for the set of NCI test chemicals vary over many orders of magnitude, it necessarily follows statistically that the carcinogenic potencies will be highly correlated. This "artifact" of potency estimation does not imply that there is no basis for extrapolating animal results to man. It does suggest, however, that the interpretation of correlation studies of carcinogenic potency needs much further thought.

Animals↗
PubMed1984

The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments.

A generally accepted format for the numerical description of the carcinogenic potency of a particular chemical in a particular strain of animals is desirable so that statements from different sources about potency and attempts by different authors to correlate potency with particular laboratory measurements will be comparable. The choice of an appropriate standard format is to a certain extent arbitrary. In this paper we recommend that the TD50 (tumorigenic dose rate 50) be used. TD50 can be calculated for a single target site or combination of sites. The TD50, in analogy with the LD50, is defined as that chronic dose rate (in mg/kg body weight/day) which would halve the actuarially adjusted percentage of tumor-free animals at the end of a standard experiment time--the "standard lifespan" for the species. This paper consists of a brief discussion of the TD50, sufficient to make the general reader familiar with the properties of such an index, an appendix discussing methods for its estimation and certain conventions we have adopted for use in analyzing "nonstandard" experiments. A major problem in calculating any index of carcinogenic potency is that much published material gives only the final crude percentage of tumor-bearing animals at each dose, instead of percentages adjusted for the effects of intercurrent mortality or data from which these adjusted percentages can be derived. If the dose level administered to the animals is toxic, then premature death from nonneoplastic causes may prevent some dosed animals that would have developed tumors from actually doing so. This will particularly affect the high-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

A carcinogenic potency database of the standardized results of animal bioassays.

The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold.

Animals↗
PubMedDate not supplied

Endogenous mutagens and the causes of aging and cancer.

A very large oxidative damage rate to DNA occurs as part of normal metabolism. In each rat cell the steady-state level is estimated to be about 10(6) oxidative adducts and about 10(5) new adducts are formed daily. It is argued that this endogenous DNA damage is a major contributor to aging and the degenerative diseases of aging, such as cancer. The oxidative damage rate in mammalian species with a high metabolic rate, short life span, and high age-specific cancer rate is much higher than the rate in humans, a long-lived creature with a lower metabolic rate and a lower age-specific cancer rate. It is argued that deficiency of micronutrients, such as dietary antioxidants or folate, is a major contributor to human cancer and degenerative diseases. Understanding the role of mitogenesis in mutagenesis is critical for clarifying the mechanisms of carcinogenesis and interpreting high-dose animal cancer tests. High-dose animal cancer tests have been done mainly on synthetic industrial chemicals, yet almost all of the chemicals humans are exposed to are natural. About half of natural chemicals tested in high-dose animal cancer tests are rodent carcinogens, a finding that is consistent with the view that high-dose tests frequently increase mitogenesis rates. Animals have numerous defenses against toxins that make them very well buffered against low doses of almost all toxins, whether synthetic or natural.

Aging↗