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J I Goodman

Publications and source records attributed to J I Goodman.

At least 37 records · Page 2Linked to original sources
PubMed1998

The traditional toxicologic paradigm is correct: dose influences mechanism.

Dose influences mechanism; and over a wide range of doses, one can envision that mechanism will change with changing dose. This basic concept in toxicology is juxtaposed with the biologic importance of maintaining normal DNA methylation status to provide the focus of this paper. The idea that altered DNA methylation plays a variety of roles in carcinogenesis is compatible with three key features of this multistage process: clonal selection of abnormal cells in a progressive fashion, the reversibility of tumor promotion, and the multiplicity of tumor phenotypes. A relatively low capacity to maintain normal methylation status appears to explain, in part, the high propensity of the B6C3F1 mouse to develop liver tumors. This observation supports the view that a mouse liver tumor response is not an appropriate end point for human risk assessment. Additionally, it is suggested that altered DNA methylation can be viewed as a secondary mechanism underlying carcinogenesis. The knowledge that a chemical is acting by a mode of action involving a secondary mechanism can be used to support a safety factor or multiplicity of exposure approach to risk assessment.

Animals↗
PubMed1997

5-methylcytosine is present in the 5' flanking region of Ha-ras in mouse liver and increases with ageing.

Modifications to DNA-5-methylcytosine (5MeC) content (i.e., alterations in the level of 5MeC) constitute epigenetic events. In general, hypomethylation of a gene is necessary but not sufficient for expression, while methylated genes typically are quiescent. Ha-ras is an oncogene commonly implicated in murine liver tumorigenesis, often, though not always, involving mutation. A PCR-based approach using pre-PCR digestion with methylation-sensitive enzymes was employed to determine the 5MeC content of the 5' flanking region of this gene in (i) B6C3F1 and C57BL/6 mouse liver from young animals (4 months old) and (ii) B6C3F1 mouse liver from aged animals (24 months old). Two segments of the 5' flanking region of Ha-ras were examined. We demonstrate the presence of 5MeC in a portion of the 5' flanking region of Ha-ras that does not share characteristics of a CpG island, while a region that shares CpG island characteristics is primarily unmethylated. Differences in methylation status in these areas of Ha-ras were not observed between B6C3F1 and C57BL/6 mouse livers. Increases in methylation status were observed with ageing in B6C3F1 mouse liver. These data provide a role for methylation in regulating Ha-ras expression in mouse liver. Ha-ras in human liver has been reported to be unmethylated. There are substantial sequence differences in a key region of the 5' flanking region of Ha-ras in mice as compared to humans. These differences in DNA methylation and sequence may, in part, provide a basis for the frequent involvement of Ha-ras in mouse liver tumors and its virtual lack of involvement in human tumors.

5-Methylcytosine↗
PubMed1997

Comparison of effect of tumor promoter treatments on DNA methylation status and gene expression in B6C3F1 and C57BL/6 mouse liver and in B6C3F1 mouse liver tumors.

The effects of different liver tumor-promoting treatments (i.e., a choline-devoid, methionine-deficient (CMD) diet, phenobarbital (PB), or both) on Ha-ras and raf methylation status and expression were determined in mouse strains with different susceptibilities to liver tumor formation: the relatively sensitive B6C3F1 and the relatively resistant C57BL/6. Additionally, B6C3F1 mouse liver tumors, spontaneous or PB induced, were assessed for alterations in global DNA methylation status and expression of Ha-ras and raf. The CMD diet led to hypomethylation of Ha-ras and raf after 12 wk of administration in B6C3F1 and C57BL/6 mice. At this early phase of tumor promotion, the frequency of increased expression of both Ha-ras and raf mRNAs was higher in the B6C3F1 but not the C57BL/6 mice. This is a mechanism that may, in part, underlie the heightened sensitivity of the B6C3F1 mouse to liver tumorigenesis. Subpopulations of B6C3F1 mouse liver tumors displayed altered global methylation status, with both hypomethylation and hypermethylation evident. Carcinomas were significantly more hypomethylated than adenomas. The level of raf mRNA was not changed in spontaneous or PB-induced B6C3F1 mouse liver tumors. Increased expression of Ha-ras was evident in some spontaneous B6C3F1 liver tumors and in most of the PB-induced liver tumors. These experiments support the concept that altered DNA methylation plays a key role in tumorigenesis and indicate that the high propensity of the B6C3F1 mice to liver tumorigenesis may be due, in part, to a decreased ability to maintain normal methylation status.

Animals↗
PubMed1997

Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data.

A workshop entitled "Implementation of EPA Revised Cancer Assessment Guidelines: Incorporation of Mechanistic and Pharmacokinetic Data" was held in Anaheim, California, in 1996 at the 35th Annual Meeting of the Society of Toxicology (SOT). This workshop was jointly sponsored by the Carcinogenesis, Risk Assessment, and Veterinary Specialty Sections of the SOT. The thrust of the workshop was to discuss the scientific basis for the revisions to the EPA Guidelines for cancer assessment and EPA's plans for their implementation. This is the first revision to the original EPA guidelines which have been in use by EPA since 1986. The principal revisions are intended to provide a framework for an increased ability to incorporate biological data into the risk assessment process. Two cases were presented, for chloroform and triclioroethylene, that demonstrated the use of the revised guidelines for specific cancer risk assessments. Using these new guidelines, nonlinear margin of exposure analyses were proposed for these chemicals instead of the linearized multistage model previously used by the EPA as the default method. The workshop participants generally applauded the planned revisions to the EPA guidelines. For the most part, they considered that the revised guidelines represented a positive step which should allow for and encourage the use of biological information in the conduct of cancer risk assessments. Several participants cautioned however that the major problem with cancer risk assessments would continue to be the inadequacy of available data on which to conduct more scientific risk assessments.

Animals↗
PubMed1997

The FEMA GRAS assessment of furfural used as a flavour ingredient. Flavor and Extract Manufacturers' Association.

The Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA) has assessed the safety of furfural for its continued use as a flavour ingredient. The safety assessment takes into account the current scientific information on exposure, metabolism, pharmacokinetics, toxicology, carcinogenicity and genotoxicity. Furfural was reaffirmed as GRAS (GRASr) as a flavour ingredient under conditions of intended use based on: (1) its mode of metabolic detoxication in humans; (2) its low level of flavour use compared with higher intake levels as a naturally occurring component of food; (3) the safety factor calculated from results of subchronic and chronic studies, (4) the lack of reactivity with DNA; and (5) the conclusion that the only statistically significant finding in the 2-year NTP bioassays, an increased incidence of hepatocellular adenomas and carcinomas in the high-dose group of male mice, was secondary to pronounced hepatotoxicity. Taken together, these data do not indicate any risk to human health under conditions of use as a flavour ingredient. This evidence of safety is supported by the occurrence of furfural as a natural component of traditional foods, at concentrations in the diet resulting in a 'natural intake' that is at least 100 times higher than the intake of furfural from use as a flavour ingredient.

Adenoma, Liver Cell↗
PubMed1996

Workshop overview. National Toxicology Program Studies: principles of dose selection and applications to mechanistic based risk assessment.

A workshop entitled "NTP Studies: Principles of Dose Selection and Applications to Mechanistic Based Risk Assessment" was held at the 34th Annual Meeting of the Society of Toxicology in Baltimore, Maryland. The purpose of the workshop was to provide an overview of factors currently considered important in the selection of doses for NTP studies, to describe some of the confounding factors that can result from the indiscriminate use of bioassay data in quantitative risk assessment, and to suggest ways in which information from mechanistic studies or studies of biomarkers of exposure or effect might be used to better advantage in risk assessment.

Biomarkers↗
PubMed1995

An analysis of the National Toxicology Program's (NTP) Technical Report (NTP TR 421) on the toxicology and carcinogenesis studies of talc.

The NTP toxicology and carcinogenicity studies of nonasbestiform, cosmetic-grade talc (the NTP Talc Report) were conducted by exposing male and female F344/N rats and B6C3F1 mice to target aerosol concentrations of 0, 6, and 18 mg/m3 talc for 6 hr daily, 5 days per week. Based on results of the high dose, the Report concluded that talc caused lung tumors in female rats and pheochromocytomas in male and female rats, and there was no evidence of carcinogenic activity in mice. A thorough evaluation of lung toxicity revealed that talc-induced lung tumors occurred only in the group of animals that exhibited the most profound degree of chronic toxicity. However, these data were presented as empirical observations rather than discussed in a manner that would relate them to the risk assessment implications of the bioassay, i.e., relevant data were collected but not "used." In addition, the evaluation of the pheochromocytomas was inadequate because it failed to place sufficient emphasis on the spontaneous incidence of this tumor in rats. These deficiencies caused the author to vote against the conclusions presented in the Talc Report when it was reviewed by the NTP Board of Scientific Counselors. The appropriate conclusions are (1) the data do not indicate that the pheochromocytomas were treatment-related; (2) the maximum tolerated dose (MTD) was exceeded in the female rats exposed to the high dose; and (3) talc is not expected to cause lung tumors under conditions of exposure that fail to result in marked chronic lung toxicity.

Adrenal Gland Neoplasms↗
PubMed1995

Principles underlying dose selection for, and extrapolation from, the carcinogen bioassay: dose influences mechanism.

The purpose of the bioassay is not to simply find chemicals that can be labeled as carcinogens. On the contrary, the overall goal is to provide a reasonable assessment of the possible hazard that a chemical might pose to people under realistic conditions of exposure. This paper focuses upon the doses commonly used in the bioassay within the context that dose influences mechanism and, over a wide range of doses, mechanism changes with changing dose. Thus, a carcinogenic effect observed at a high dose is not necessarily expected to occur at lower doses. A variety of examples are provided to illustrate the points that (a) any high dose, no matter how high, that permits test animals to live long enough to develop tumors is not an appropriate criterion for defining an acceptable high dose to employ in a carcinogen bioassay; and (b) emphasis should be placed upon research that may discern probable thresholds for the carcinogenic effect of chemicals, especially nongenotoxic chemicals.

Animals↗
PubMed1995

Hypomethylation of DNA: a nongenotoxic mechanism involved in tumor promotion.

There is an abundant amount of information on the mechanisms of action of genotoxic chemicals that act as carcinogens and the role that mutations play in carcinogenesis. However, carcinogenesis is more than mutagenesis and many carcinogens are not mutagens. Thus, there is a need to consider nongenotoxic mechanisms that may be involved in carcinogenesis. In this paper, we review our working hypothesis that hypomethylation of DNA is an epigenetic, nongenotoxic mechanism that plays a role in tumor promotion by facilitating aberrant gene expression. The utility of employing experimental models that focus on relevant comparisons between sensitive and resistant strains of mice is emphasized. Additionally, aspects of DNA methylation in rodents and humans are compared and contrasted. We discuss hypomethylation of DNA as a secondary mechanism, that is expected to be threshold-exhibiting, and conclude by describing how this information may facilitate a rational approach towards risk assessment when dealing with nongenotoxic compounds that are carcinogenic in a bioassay.

Animals↗
PubMed1995

Hypomethylation of DNA: a possible epigenetic mechanism involved in tumor promotion.

The overall objective of our research is to discern mechanisms that can facilitate the aberrant expression of oncogenes involved in carcinogenesis. We are testing the hypothesis that hypomethylation of DNA is a nongenotoxic mechanism underlying the aberrant expression of oncogenes involved in carcinogenesis. Hypomethylation may be a mechanism underlying the role of cell proliferation in carcinogenesis, and hypomethylation could possibly result from an enzymatic replacement of 5-methylcytosine (5MeC) with cytosine that is not linked to DNA replication. The testing of this hypothesis can serve as a focal point for a mechanism of action-oriented approach for considering key aspects of carcinogenesis: aberrant gene expression, heritable epigenetic events, species-to-species extrapolation/unique species sensitivity, tumor promotion, and thresholds. DNA methylation plays a role in the regulation of gene activity. There is a persuasive body of evidence indicating that differential methylation of DNA (i.e., 5-methylcytosine v. cytosine) is a determinant of chromatin structure and that the methyl group provides a chemical signal which is recognized by trans-acting factors that regulate transcription. Hypomethylation of a gene is necessary but not sufficient for its expression and, therefore, a hypomethylated gene can be considered to possess an increased potential for expression as compared to a hypermethylated gene. Changes in the methylation status of a gene provide a mechanism by which its potential for expression can be altered in an epigenetic heritable manner, and it is expected that modifications in DNA methylation would result from threshold-exhibiting events. Our experimental model is liver tumorigenesis, we focus upon oncogenes (e.g., Ha-ras and raf) relevant to mouse liver tumorigenesis, employ the liver tumor prone B6C3F1 (C57BL/6 x C3H/He) mouse, and make relevant comparisons with the sensitive C3H/He paternal strain and the resistant C57BL/6 maternal strain. A unique aspect of this research is that it offers the potential to provide insight regarding molecular mechanisms that underlie promotion of carcinogenesis while at the same time the results can provide the type of information that is required in order to take a more rational approach towards carcinogen risk assessment. Specifically, the practical significance of our research is that it addresses the areas of dose-response relationships, e.g., the existence of threshold-exhibiting mechanisms, and species-to-species extrapolation issues. This is discussed within the context of the requirement for a rational approach to risk assessment.

Animals↗
PubMed1994

Spontaneous mutation at codon 61 of the Ha-ras gene in the nascent liver of B6C3F1, C3H/He and C57BL/6 mice.

DNA was isolated from the liver of young B6C3F1, C3H/He and C57BL/6 mice, 6-9 weeks old. A portion of exon 2 of Ha-ras was amplified by PCR allele-specific amplification. The PCR product was identified by (a) size, (b) presence of a diagnostic restriction site, and (c) direct sequencing. Our results indicate that nascent mouse liver bears a subpopulation of cells which contain a mutation in codon 61 of Ha-ras, specifically an A to G transition at position 2. Therefore, the detection of this mutation in chemically induced mouse liver tumors does not demonstrate that the chemical in question acts as a mutagen. It might act by a nongenotoxic mechanism, i.e., by facilitating a clonal expression of cells bearing this spontaneous mutation.

Animals↗
PubMed1994

Alterations in the methylation status and expression of the raf oncogene in phenobarbital-induced and spontaneous B6C3F1 mouse liver tumors.

The liver tumor-prone B6C3F1 mouse (C57Bl/6 female x C3H/He male), in conjunction with the more susceptible C3H/He paternal strain and the resistant C57BL/6 maternal strain, is an excellent model for studying the mechanisms involved in carcinogenesis. The study reported here indicated that the B6C3F1 mouse inherited a maternal raf allele containing a methylated site not present in the paternal allele. Seven days after partial hepatectomy or after administration of a promoting dose of phenobarbital (PB) for 14 d; raf in B6C3F1 mouse liver was hypomethylated. The additional methylated site in the allele inherited from C57BL/6 was not maintained. The methylation status of raf in the liver of the C57BL/6 mouse was not affected by PB treatment. This indicates that the B6C3F1 mouse is less capable of maintaining methylation of raf than the C57BL/6 strain is. In both PB-induced and spontaneous B6C3F1 liver tumors, raf was hypomethylated in a nonrandom fashion. The level of raf mRNA increased in seven of 10 PB-induced tumors but in only one of five spontaneous tumors, whereas the level of Ha-ras mRNA increased in nine of 10 PB-induced tumors and in four of five spontaneous tumors. The results of our investigation (a) support the hypothesis that hypomethylation of DNA is a nongenotoxic mechanism involved in tumorigenesis, (b) support the notion that PB promotes liver tumors that develop along a pathway different from that leading to spontaneous tumors, and (c) indicate that differences in DNA methylation between C57BL/6 and B6C3F1 mice could, in part, account for the unusually high tendency of the latter strain to develop liver tumors.

Animals↗
PubMed1994

A rational approach to risk assessment requires the use of biological information: an analysis of the National Toxicology Program (NTP), final report of the advisory review by the NTP Board of Scientific Counselors.

The National Toxicology Program (NTP) Board of Scientific Counselors met on April 14 and 15, 1992 to review the NTP. This paper provides an overview of the Board's Report with an emphasis on the recommendations made by the Carcinogenesis Working Group. The prime overall recommendation is that the NTP should move from a focus on hazard identification to an emphasis on providing the type of biological information that needs to be incorporated into the risk assessment process. This would involve a hypothesis-driven mechanism of action approach aimed at understanding the basis for the actions of the chemicals of interest. Relevant examples are provided. Scientists from the National Institute of Environmental Health Sciences' (NIEHS) intramural program and those outside of NIEHS should be included in the research effort. This strategy would permit a more rational approach toward both test development and design (e.g., selection of the high dose to be employed), and the interpretation of test results (e.g., addressing questions pertaining to dose-response relationships and species to species extrapolation). The overall goal would be to provide a reasonable assessment of the possible hazard that a chemical might pose to people in light of realistic conditions of exposure.

Animals↗