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R H Reitz

Publications and source records attributed to R H Reitz.

At least 37 records · Page 2Linked to original sources
PubMed1987

Physiologically based pharmacokinetics and the risk assessment process for methylene chloride.

Methylene chloride (dichloromethane, DCM) is metabolized by two pathways: one dependent on oxidation by mixed function oxidases (MFO) and the other dependent on glutathione S-transferases (GST). A physiologically based pharmacokinetic (PB-PK) model based on knowledge of these pathways was used to describe the metabolism of DCM in four mammalian species (mouse, rat, hamster, and humans). Kinetic constants for the model were derived from in vivo experiments or the literature. The model was constructed to distinguish contributions from the two pathways of metabolism in lung and liver tissue, and to permit extrapolation from rodents to humans. Model validation was conducted by comparing predicted blood concentration time-course data in rats, mice, and humans with experimental data from these species. The tumor incidence in two chronic studies of DCM toxicity in mice was correlated with various measures of target tissue dose calculated with the PB-PK model. Tumor incidence correlated well with tissue AUC (area under the concentration/time curve) and amount of DCM metabolized by the GST pathway. However, tumor incidence did not correlate with the amount of DCM metabolized by the MFO pathway. Because of its low chemical reactivity, DCM is unlikely to be directly involved in carcinogenesis. Consequently, metabolism of DCM by GST appears to be important in carcinogenesis. The PB-PK model was used to estimate target doses of presumed toxic chemical species in humans exposed to DCM by inhalation or by drinking water. Target tissue doses in humans exposed to low concentrations of DCM are 140- to 170-fold lower (inhalation) or 50- to 210-fold lower (drinking water) than would be expected from the linear extrapolation and body surface area factors which have been used in conventional risk assessment methods (D. V. Singh, H. L. Spitzer, and P. D. White (1985). Addendum to the Health Assessment Document for Dichloromethane (Methylene Chloride). EPA/600/8-82/004F). The PB-BK analysis thus suggests that conventional risk analyses greatly overestimate the risk in humans exposed to low concentrations of DCM. PB-PK considerations provide a scientific basis for risk assessment, improve experimental design in chronic studies, and structure collection of quantitative metabolic constants required for risk assessment.

Animals↗
PubMed1987

Research strategy in industrial toxicology.

While much of industrial toxicology is observational in character, pursuit of specific research is needed to facilitate the overall evaluation of potential toxicity for man. Two such areas are the application of physiologic pharmacokinetic models to inter-species extrapolation of toxic effects and an understanding of the role of cellular oncogenes in the process of spontaneous tumor formation in animals. A physiologic pharmacokinetic model was developed for methylene chloride (MeCl2) which describes the fate of MeCl2 and its metabolic products in numerous species including the mouse, rat, hamster and man. This model has been used to predict specific tissue concentrations of critical metabolic reaction products in target tissues between animals and man. If it is assumed that toxicity is related to target tissue concentrations such methodology provides a means of relating interspecies toxicity to absorbed dose. This methodology precludes the necessity of using arbitrary factors in relating animal toxicity data to man. A particular controversial issue in animal toxicology is the significance of the enhancement of animal tumors in tissues which already have a high spontaneous incidence. Without a better understanding of the basic process of spontaneous tumor formation it remains difficult to interpret results from chemical treatment. In particular spontaneous liver tumors in the B6C3F1 mouse have been shown to contain an activated cellular oncogene identified as H-RAS. The activated cellular oncogene is present in tumor tissue only and not in surrounding normal liver tissue. Of particular significance is the high frequency of activation in these mouse liver tumors (82%) compared to a 10-20% incidence of oncogenes present in a variety of human tumors. This suggests the ultra sensitivity of this mouse strain to liver tumor induction. Additional studies in progress are designed to determine whether genotoxic and nongenotoxic hepatocarcinogens show differences in oncogene activation.

Animals↗
PubMed1984

Biochemical factors involved in the effects of orthophenylphenol (OPP) and sodium orthophenylphenate (SOPP) on the urinary tract of male F344 rats.

Carbon-14 labeled sodium orthophenylphenate (SOPP) was incubated with purified microsomes isolated from rat liver. During this incubation, macromolecular binding of radioactivity (MMB) was observed. MMB was dependent upon the presence of both active microsomes and NADP. In vivo studies of MMB were also conducted. MMB was measured in the liver, kidney, and bladder of male F344 rats administered SOPP (0.19 to 1.88 mM/kg) or orthophenylphenol (OPP) (0.29 to 2.97 mM/kg). The levels of MMB were not linearly related to administered dose. Disproportionate increases in MMB were observed in each tissue after administration of 0.75 to 1.88 mM/kg of SOPP. Disproportionate increases in MMB in liver and bladder tissue were also observed with OPP at somewhat higher doses. These studies indicate that the intermediate(s) produced by the oxidative pathway for metabolism of SOPP and OPP are capable of binding to biological macromolecules. The disproportionate increases in MMB observed in vivo after high doses are probably associated with saturation of the primary (conjugative) metabolic pathway for SOPP and OPP metabolism.

Animals↗
PubMed1983

Importance of non-genetic mechanisms in carcinogenicity.

Integration of all this data suggests that the tumors reported by Hiraga and Fujii are related to the cytotoxicity induced in bladder epithelial tissue when primary metabolic pathways are overloaded by administration of high doses of SOPP . However, this appears to be a SECONDARY consequence of toxicity, rather than any PRIMARY effect upon DNA. Consequently, it appears that there is little chance for inducing bladder tumors with OPP or SOPP unless exposure levels are high enough to saturate primary metabolic pathways.

Animals↗
PubMed1982

Mechanistic considerations for carcinogenic risk estimation: chloroform.

Chloroform has been reported to induce cancer in rodents after chronic administration of high doses by gavage. However, the interpretation of these findings is hampered by a lack of knowledge concerning the relative roles of genetic and nongenetic mechanisms in these bioassays. The present studies were carried out in male B6C3F1 mice in order to investigate the potential of chloroform to induce genetic damage and/or organ toxicity at the sites where tumors have been observed in the various bioassays. These studies revealed that carcinogenic doses of chloroform produced severe necrosis at the sites where tumors later developed. This was demonstrated by light microscopy as well as by determination of the cellular regeneration index following administration of 3H-thymidine. Noncarcinogenic doses of chloroform failed to induce these responses. In contrast, studies of DNA alkylation and DNA repair in vivo failed to give any indication that chloroform had produced the type of genetic alterations associated with known genotoxic chemicals. These data suggest that the primary mechanism of chloroform-induced carcinogenesis is nongenetic in nature. If the same mechanism predominates in man, there should be little to no carcinogenic risk associated with exposure to noncytotoxic levels of chloroform.

Alkylation↗
PubMed1980

Non-linear pharmacokinetic parameters need to be considered in high dose/low dose extrapolation.

It is impossible to prove that any chemical, natural or man-made, cannot cause cancer in man. However, it is possible to estimate the relative degrees of risk associated with various agents. The precision of these estimations increases as experimental procedures elucidate the basic type of mechanism associated with carcinogenesis, the role of absorption, metabolism and distribution, and excretion in increasing or decreasing activity, and the dose dependency of metabolic pathways. We must constantly strive to make the most accurate risk estimations possible so that the complex issues of risk/benefit may be properly considered.

Alkylation↗