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Robert Kavlock

Publications and source records attributed to Robert Kavlock.

14 recordsLinked to original sources
PubMed2006

Implications of gender differences for human health risk assessment and toxicology.

This paper from The Human Health working group of SGOMSEC 16 examines a broad range of issues on gender effects in toxicology. Gender differences in toxicology begin at the gamete and embryo stage, continuing through development and maturation and into old age. Sex influences exposure, toxicokinetics, and toxicodynamics. The effects of sex have often been overlooked in both epidemiology and toxicology. In addition to the obvious modifying effects of the sex hormones and conditions affecting the male and female reproductive organs and sex roles, both genetic and hormonal effects influence many aspects of life and toxic responses. All aspects of toxicology should consider gender-balanced designs so that a more comprehensive understanding of differences and similarities can be obtained. Differential gene expression is a new frontier in toxicology. Risk assessment should account for gender and life cycle differences. The biological basis for altered sex ratios observed in several populations should be sought in animal models, and expanded to other compounds that might exert sex-selective effects. Wherever possible and feasible, toxicologic and environmental epidemiological studies should be designed and have sufficient statistical power to quantify differential gender-based exposures and outcomes.

Bone and Bones↗
PubMedDate not supplied

A systems biology approach to developmental toxicology.

Recent advances in developmental biology have yielded detailed models of gene regulatory networks (GRNs) involved in cell specification and other processes in embryonic differentiation. Such networks form the bedrock on which a systems biology approach to developmental toxicology can be built. In this review, an introduction to GRNs in general is followed by a description of specific networks involved in sea urchin and Drosophila development. A hypothesis is presented regarding the role of GRN analysis in the determination of mechanisms of chemical toxicity during embryonic development. Potential for future directions and research approaches in this area is discussed.

Animals↗
PubMedDate not supplied

Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data.

A complete mode of action human relevance analysis--as distinct from mode of action (MOA) analysis alone--depends on robust information on the animal MOA, as well as systematic comparison of the animal data with corresponding information from humans. In November 2003, the International Life Sciences Institute's Risk Science Institute (ILSI RSI) published a 2-year study using animal and human MOA information to generate a four-part Human Relevance Framework (HRF) for systematic and transparent analysis of MOA data and information. Based mainly on non-DNA-reactive carcinogens, the HRF features a "concordance" analysis of MOA information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. With MOA information increasingly available for risk assessment purposes, this article illustrates the further applicability of the HRF for reproductive, developmental, neurologic, and renal endpoints, as well as cancer. Based on qualitative and quantitative MOA considerations, the MOA/human relevance analysis also contributes to identifying data needs and issues essential for the dose-response and exposure assessment steps in the overall risk assessment.

Aging↗
PubMedDate not supplied

Mode of action: inhibition of androgen receptor function--vinclozolin-induced malformations in reproductive development.

Vinclozolin is a fungicide that has been shown to cause Leydig cell tumors and atrophy of the accessory sex glands in adult rodents. In addition, exposure of rats during pregnancy causes a pattern of malformations in the male urogenital tract. A wealth of standard toxicological studies and targeted research efforts is available related to this adverse effect, and these were used to evaluate the Human Relevance Framework (HRF) for noncancer health effects. Vinclozolin and two of its metabolites, designated M1 and M2, have been shown to bind and inhibit the function of the rat and human androgen receptor. Other means of interfering with androgen receptor function (e.g., by exposure to the pharmaceutical agent flutamide) lead to similar adverse health outcomes. There is direct in vivo evidence in the rat prostate that androgen-dependent gene expression changes occur after exposure to vinclozolin. There are no proposed alternatives to the androgen receptor-mediated mode of action. Based on what is known about kinetic and dynamic factors, confidence is high that the animal mode of action (MOA) for vinclozolin-induced malformation of the male reproductive tract is highly plausible in humans.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Mode of action: reduction of testosterone availability--molinate-induced inhibition of spermatogenesis.

Molinate is a preemergent herbicide that has been demonstrated to affect reproduction in the rat via alterations in sperm production. A wealth of standard toxicological studies and targeted research efforts relating to this adverse effect is available, and these were used to evaluate the utility of the Human Relevance Framework (HRF) for noncancer health effects. The hypothesized mode of action involved inhibition of the hydrolysis of cholesterol from high-density lipoprotein in the rat testes, followed by an androgen withdrawal syndrome on spermatogenesis. Some evidence is available that a similar mode of action would not be operable in humans. Despite the wealth of studies conducted in the rat, the weight of evidence is insufficient to define the mode of action for reproductive toxicity in the male rat. A principal deficiency in the database was discordance between the exposure levels observed to cause biochemical disturbances in the testes related to the hypothesized mode of action and the dose levels observed to induce the adverse outcome on spermatogenesis. For this reason, a complete MOA/human relevance analysis is not possible and, based on traditional risk assessment principles, any toxic effects are assumed to be relevant for human risk assessment.

Animals↗