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Biomedical subjects

J K Haseman

Publications and source records attributed to J K Haseman.

At least 145 records · Page 8Linked to original sources
PubMed1983

The carcinogenicity of di(2-ethylhexyl) phthalate (DEHP) in perspective.

The commonly used plasticizer di(2-ethylhexyl) phthalate (DEHP) was recently tested for chronic toxic potential by incorporation into the diet of rats and mice for approximately 2 yr. Upon reviewing the test results, the sponsoring organization concluded that DEHP was carcinogenic to the rats and mice, as indicated by increased occurrences of liver tumors in the DEHP-exposed animals in comparison to controls. Another group has disagreed with this conclusion, however, citing perceived methodological deficiencies and improper interpretations in the study, and has also suggested that rodents may not be adequate models of human response to DEHP. This communication compares the conduct of the DEHP bioassay favorably with state-of-the-art procedures in animal carcinogenicity testing and documents approval of the study interpretations by several independent peer review groups. The carcinogenic potential of DEHP is placed in perspective by evaluating the evidence for DEHP-induced tumors in rodent species in light of dose response relationships, other biochemical and toxicological effects of DEHP, and its comparative metabolism and disposition in rodent and primate species. A composite analysis of the currently available information indicates that DEHP has been shown to be carcinogenic to rodents in a valid chronic test, indicating that it should be considered as a potential carcinogen in humans, as well. Further experimental inquiry will be required, however, to accurately assess the potential health risks posed to humans by exposure to small amounts of this plasticizer.

Animals↗
PubMed1983

Statistical support of the proposed National Toxicology Program protocol.

Statistical issues related to the design, analysis and interpretation of carcinogenicity studies are considered. A proposed modification of the "standard" National Cancer Institute (NCI) design of carcinogenicity studies in rodents is discussed. The primary objective was to obtain a design that maintained the power of the NCI design for detecting carcinogenic effects, while increasing the precision with which the underlying dose-response model could be estimated. "Optimum" three-dose designs are presented and discussed. Data analysis issues are also considered. Comparisons of tumor incidence should include adjustments for survival differences, and, if possible, cause of death determinations should be made for each individual animal. In some instances historical control data can aid an investigator in the overall evaluation of experimental results. Several important problems are discussed that must be overcome before historical control data can be used in a meaningful way. One critical issue in the interpretation of tumor incidence data is the issue of false positives. Data from 25 recent long term feeding studies are used to derive a statistical decision rule that closely approximates the scientific judgment process used in these studies. The overall false positive rate associated with this decision rule was found to be no more than 7-8%.

Animals↗
PubMed1982

Carcinogenicity testing of phthalate esters and related compounds by the National Toxicology Program and the National Cancer Institute.

Five phthalate ester and related compounds (phthalic anhydride, phthalamide, di(2-ethylhexyl) phthalate, di(2-ethylhexyl) adipate and butyl benzyl phthalate) have been tested for carcinogenic effects in standard lifetime rodent feeding studies. Groups of 50 male and female rats and mice were fed diets containing various concentrations of the test chemicals for 102-106 consecutive weeks. The dietary concentrations were estimated to be maximally tolerated doses and half maximally tolerated doses. All animals that died during the study and all survivors at the end of two years were examined grossly and microscopically for the presence of tumors. The incidences of animals with tumors at a specific anatomic site in the treated groups and the controls were compared statistically. Neither phthalamide nor phthalic anhydride increased tumor incidences in rats or mice. Di(2-ethylhexyl) phthalate increased the incidences of liver tumors in rats and mice of both sexes, while di(2-ethylhexyl) adipate caused liver tumors in male and female mice, only. Butyl benzyl phthalate did not cause tumors in male or female mice, but the incidence of myelomonocytic leukemia in butyl benzyl phthalate-treated female rats was significantly greater than that in the controls. Chemically induced early deaths in the butyl benzyl phthalate-treated male rats precluded an evaluation of carcinogenic potential in this sex. Under the conditions of these tests, di(2-ethylhexyl) adipate was considered to be carcinogenic in both rats and mice and di(2-ethylhexyl) adipate was considered to be carcinogenic in mice. The evidence for carcinogenic effects of butyl benzyl phthalate in female rats was judged to be equivocal because of the variable nature of the incidence of myelomonocytic leukemia in Fischer 344 rats. Phthalamide and phthalic anhydride did not exhibit carcinogenic effects in these studies.

Animals↗
PubMed1981

Some practical problems arising from use of the gamma multihit model for risk estimation.

The Scientific Committee of the Food Safety Council recently recommended use of the gamma multihit model for risk assessment. Some practical problems arising from the use of this model are presented. In some instances the model produces what appear to be unreasonably high "safe dose" estimates. In other instances the estimates appear unrealistically low. Neither the original "standard" nor the "conservative" confidence limits seem adequate for practical application. The assumptions leading to the use of Abbott's correction are difficult to verify, but have a great effect on safe dose estimates. Indeed, the introduction of as little as 1% additive background into the gamma multihit model leads to safe dose estimates closer to those produced by the Armitage-Doll model than to those of the pure gamma multihit model.

Aflatoxin B1↗
PubMed1980

Dose response of 1,2-dimethylhydrazine and methylazoxymethanol acetate in the F 344 rat.

Weanling male and female F 344 rats were given various doses of 1,2-dimethylhydrazine (DMH) or methylazoxymethyl acetate (MAMAc), and were then held for 46-64 weeks in an effort to determine a dose response and establish a dose level which would produce a low level of intestinal neoplasia with a minimal number of tumors in other organs. DMH proved superior to MAM in this respect, although liver lesions were still observed with both compounds at the lowest carcinogenic intestinal dose.

Animals↗
PubMed1979

Statistical tests for recessive lethal-carriers.

This paper presents a statistical method for testing whether a male mouse is a recessive lethal-carrier. The analysis is based on a back-cross experiment in which the male mouse is mated with some of his daughters. The numbers of total implantations and intrauterine deaths in each litter are recorded. It is assumed that, conditional on the number of total implantations, the number of intrauterine deaths follows a binomial distribution. Using computer-simulated experimentation it is shown that the proposed statistical method, which is sensitive to the pattern of intrauterine death rates, is more powerful than a test based only on the total number of implant deaths. The proposed test requires relatively simple calculations and can be used for a wide range of values of total implantations and background implant mortality rates. For computer-simulated experiments, there was no practical difference between the empirical error rate and the nominal error rate.

Animals↗
PubMed1979

Increased frequencies of aberrant sperm as indicators of mutagenic damage in mice.

We have tested the effects of TEM in 3 strains of mice using the sperm morphology assay. In addition, we have made an attempt to evaluate this test system with respect to experimental design, statistical problems and possible interlaboratory differences. Treatment with TEM results in significant increases in the percent of abnormally shaped sperm. These increases are readily detectable in sperm treated as spermatocytes and spermatogonial stages. Our data indicate possible problems associated with inter-laboratory variation in slide analysis. We have found that despite the introduction of such sources of variation, our data were consistent with respect to the effects of TEM. Another area of concern in the sperm morphology test is the presence of "outlier" animals. In our study, such animals comprised 4% of the total number of animals considered. Statistical analysis of the slides from these animals have shown that this problem can be dealt with and that when recognized as such, "outliers" do not effect the outcome of the sperm morphology assay.

Animals↗
PubMed1979

Statistical design of toxicity assays: role of genetic structure of test animal population.

This paper concerns certain statistical aspects of the problem of among-strain differences in cancer susceptibility and how these differences may affect the design of toxicity assays. First, the data of Innes et al. (1969) were examined to investigate the magnitude of within-study, between-strain differences in tumor induction. Although there was a very high overall association between mouse strains with respect to the induction of hepatomas, evidence of strain-to-strain variability was found for several compounds. Next, a number of long-term carcinogenicity studies with DDT were considered, and among-strain differences in cancer susceptibility for this compound were noted. Finally, it was shown that if susceptible subgroups do exist, and certain simplifying assumptions are made, then in many cases tumor increases can be detected more readily by studying several inbred mouse strains rather than a single outbred stock.

Animals↗
PubMed1979

Analysis of dichotomous response data from certain toxicological experiments.

In certain toxicological experiments with laboratory animals, littermate data are frequently encountered. It is generally recognized that one characteristic of this type of data is the "litter effect", i.e., the tendency for animals from the same litter to respond more alike than animals from different litters. In this paper attention is restricted to dichotomous response variables that frequently arise in toxicological studies, such as the occurrence of fetal death or a particular malformation. Various techniques for estimating the underlying probability of response are discussed. A number of generalized models that have recently been proposed to take the litter effect into account are breifly reviewed and compared to the simpler binomial and Poisson models. Various procedures for assessing the significance of treatment-control differences are presented and their relative merits discussed. Finally, future research needs in this area are outlined.

Animals↗
PubMed1978

The use of a correlated binomial model for the analysis of certain toxicological experiments.

In certain toxicological experiments with laboratory animals, the outcome of interest is the occurrence of dead or malformed fetuses in a litter. Previous investigations have shown that the simple one-parameter binomial and Poisson models generally provide poor fits to this type of binary data. In this paper, a type of correlated binomial model is proposed for use in this situation. First, the model is described in detail and is compared to a beta-binomial model proposed by Williams (1975). These two-parameter models are then contrasted for goodness of fit to some real-life data. Finally, numerical examples are given in which likelihood ratio tests based on these models are employed to assess the significance of treatment-control differences.

Abnormalities, Drug-Induced↗
PubMed1978

Alternatives to Rothman's approach for assessing synergism (or antagonism) in cohort studies.

K.J. Rothman has explored in some detail the issue of assessing the potential presence of synergism (or antagonism) in data generated from either a cohort or a case-control study. Arguing that the "natural" scale for quantifying the joint effects of two or more factors acting in combination is the probability scale, he has proposed a procedure based on a ratio-type index for evaluating two-factor interaction in the presence of non-zero background effects. In this paper, the authors review the rationale underlying Rothman's approach for a cohort study. They then present what they maintain is a simpler and more appropriate test procedure (utilizing a linear contrast of the observed risks) for the additive approximation to his basic probabilistic model of "no interaction." A likelihood ratio test based on his original model is also proposed, as well as a closed form approximation to it. Finally, the assessment of interaction in cohort studies involving exposure factors measured at more than two levels is addressed.

Epidemiology↗
PubMed1977

Identification of the individual polychlorinated biphenyls in a mixture by gas-liquid chromatography.

Retention indices were computed for all of the 210 possible chlorinated biphenyls on 13 gas chromatographic liquid phases. All possible pairwise comparisons of retention indices were made for each liquid phase, each pair of liquid phases and each set of three liquid phases. On the basis of a closeness criterion of 10 (deltaRI = RIa - RIb = 10), those combinations of three or fewer liquid phases which could distinguish between nearly all possible pairs of chlorinated biphenyls were selected. Further considerations such as column efficiencies, analysis time required, resolution achievable and availability led to the selection of several common liquid phases for the qualitative and, in some cases, quantitative analysis of the individual components of mixtures of polychlorinated biphenyls. A few specific applications are discussed.

Chromatography, Gas↗
PubMed1977

Effects in rats and guinea pigs of short-term exposures to sulfuric acid mist, ozone, and their combination.

Ozone and the oxides of sulfur are common environmental pollutants. The acute pulmonary lesions caused by ozone and sulfuric acid mist in rats and guinea pigs have been characterized. Rats are not affected by sulfuric acid mist in concentrations up to 100 mg/m3 except for reduced body weight at the higher doses. A true alveolitis develops in guinea pigs exposed to more than 20 mg/m3 sulfuric acid mist. The ozone lesion is primarily confined to the terminal bronchioles and proximal alveoli. In combination studies with up to 2 ppm ozone and up to 10 mg/m3 sulfuric acid mist, the pulmonary lesion and lung/body weight data were essentially the same as in exposure to ozone alone, and the number of statistically significant synergistic effects in rats and guinea pigs was about what one would expect to observe by chance alone.

Aerosols↗
PubMed1976

The distribution of fetal death in control mice and its implications on statistical tests for dominant lethal effects.

In dominant lethal testing fetal death is generally assumed to follow either a Poisson or binomial distribution. However, both of these models were found to be inappropriate when three large sets of mouse control data and other data sets from the literature were examined. The validity of statistical test procedures based on these inappropriate models was then studied in detail. It was found that chi-square tests (which assume an underlying binomial distribution) may seriously exaggerate the level of significance and hence should not be used. In contrast, the inappropriateness of the underlying Poisson or binomial model appeared to have little effect on the validity of pairwise comparisons by analysis of variance procedures. Unlike chi-square, these procedures regard the pregnant female rather than the individual implant as the experimental unit. However, a statistical analysis of dominant lethal data generally involves more than a series of pairwise comparisons, and it is unclear how an invalid underlying model may affect statistical test procedures in this more complex situation. Moreover, it is difficult to justify the use of statistical models that are demonstrably invalid when a reasonable alternative exists. Thus, until a satisfactory parametric model can be found and appropriate test procedures derived, we prefer to analyze dominant lethal data by non-parametric (distribution-free) methods. Proportion of dead implants per female appears to be a more meaningful measure of fetal death than number of dead implants per female for several seasons which include (1) analyses based on proportions take the total number of implants per female into account and (2) analyses based on proportions make more reasonable assumptions concerning pre-implantation losses and are more powerful when such losses occur. Despite our concern with the appropriateness of the underlying model, in practice we have found few instances in which non-parametric and analysis of variance procedures have led to markedly different conclusions.

Animals↗