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Biomedical subjects

B Schwetz

Publications and source records attributed to B Schwetz.

6 recordsLinked to original sources
PubMed1998

Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans?

The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Alternative tests: carcinogenesis as an example.

Acceptance of new tests that are alternatives to currently used toxicology tests is a topic of considerable importance in the field of toxicology. Carcinogenicity testing today normally includes 2-year studies in rats and mice of both sexes, following widely accepted procedures for husbandry; selection of dose levels; pathology and toxicity observations; and statistical interpretation of tumor data. These studies are usually preceded by tests for genetic toxicity and subchronic toxicity studies to select dose levels for the 2-year studies. Although these data are used for quantitative risk assessment, the mechanistic basis for effects is usually unknown. The series of studies is very expensive and requires 5 years or more to conduct. Alternative approaches are being developed that would provide more mechanistic information and hopefully would permit decisions to be made about carcinogenic potential without the need to conduct 2-year studies in rats and mice of both sexes. Decisions could be based on a profile of data rather than on the result of one test. Procedures for regulatory acceptance of new approaches for carcinogenicity testing are critical to future progress.

Animal Testing Alternatives↗
PubMed1998

Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans?

The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response.

Animals↗
PubMed1997

New directions for predicting carcinogenesis.

Carcinogenicity testing today normally includes conducting 2-yr studies of rats and mice of both sexes and following widely accepted procedures for husbandry, selection of dose levels, pathology and toxicity observations, and statistical interpretation of tumor data. These studies are usually preceded by tests for genetic toxicity and subchronic toxicity studies to select dose levels for the 2-yr studies. While these data are used for quantitative risk assessment, the mechanistic basis for effects is usually unknown, and such series of studies are very expensive and require five or more years to conduct. Alternate approaches are being developed that would provide more mechanistic information and perhaps would permit decisions to be made about carcinogenic potential without the need to conduct 2-yr studies of rats and mice of both sexes. Decisions could be based on a profile of data rather than the result of one test. Regulatory acceptance of new approaches for carcinogenicity testing is critical to future progress in the field of carcinogenesis.

Animals↗
PubMed1986

Effects of 1,1-dichloro-2,2-bis[p-chlorophenyl]ethylene (DDE) on lactation in rats.

An inverse correlation between the concentration of DDE in human breast milk samples and the duration of breast feeding prompted the present study of the effects of DDE administration on the lactational performance of primiparous rats. Daily doses of 10 mg p,p'-DDE/kg body weight were given to virgin female Sprague-Dawley rats 5 d/wk for 5 wk prior to mating and continued throughout the gestation and lactation periods. Lactation capacity was determined by monitoring neonatal growth and by measuring milk production, milk composition (total protein, total lipid, and lactose), and mammary-gland weight and nucleic acid content on d 9 and 20 postpartum. Gross toxicity was assessed by monitoring clinical signs and body weight of the dams, and by measuring organ weights of the dams on lactation d 9 and 20. Histopathological evaluation of the mammary glands and selected organs in the dams and pups was also performed. The dose level of DDE employed was apparently not toxic to the dams and did not have a pronounced effect on neonatal mortality. No significant differences between DDE-treated and control groups were observed for any of the lactation parameters, even though the concentration of DDE in the milk of treated rats was approximately two orders of magnitude greater than the upper range of the DDE levels measured in human milk samples. These findings indicate that DDE does not adversely affect lactation or neonatal growth in Sprague-Dawley rats at the dose level used in this study.

Animals↗