skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

Abstract

We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.

Authors:
 [1]
  1. Daniel M. Sheehan and Associates, 1422 Scott St., Little Rock, AR 72202 (United States). E-mail: dansheeh@swbell.net
Publication Date:
OSTI Identifier:
20775299
Resource Type:
Journal Article
Resource Relation:
Journal Name: Environmental Research; Journal Volume: 100; Journal Issue: 1; Other Information: DOI: 10.1016/j.envres.2005.09.002; PII: S0013-9351(05)00126-X; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL EFFECTS; ESTRADIOL; HYPOTHESIS; RISK ASSESSMENT; THRESHOLD DOSE; TURTLES

Citation Formats

Sheehan, Daniel M. No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment. United States: N. p., 2006. Web. doi:10.1016/j.envres.2005.09.002.
Sheehan, Daniel M. No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment. United States. doi:10.1016/j.envres.2005.09.002.
Sheehan, Daniel M. Sun . "No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment". United States. doi:10.1016/j.envres.2005.09.002.
@article{osti_20775299,
title = {No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment},
author = {Sheehan, Daniel M.},
abstractNote = {We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.},
doi = {10.1016/j.envres.2005.09.002},
journal = {Environmental Research},
number = 1,
volume = 100,
place = {United States},
year = {Sun Jan 15 00:00:00 EST 2006},
month = {Sun Jan 15 00:00:00 EST 2006}
}
  • Steady-state analyses of generic PBPK models for volatile organic chemical (VOC) exposure and risk assessment have been undertaken and applied for nearly two decades now. Chiu and White's paper on this subject adds little new to this earlier work. Their dismissive claim that ''Similar analyses have been done for specific chemicals and for inhalation'' is misleading, because some of this earlier work did indeed focus on ''generic'' PBPK models generally applicable to VOC exposure by multiple routes. In particular, the earliest of these previous studies developed steady-state solutions for generic PBPK models including respiratory and 1-compartment oral routes of exposure,more » and further specified how to add injection and dermal exposure routes. Chiu and White included a 2-compartment oral pathway and a lung compartment in an otherwise identical generic PBPK model, but did not consider other exposure pathways such as dermal uptake. Each of the earlier studies first presented a steady-state solution to a generic, multiroute PBPK model, and only then applied the generic solution to a problem or illustration involving a specific compound--i.e., the same approach used later by Chiu and White. For example, the earlier study included a simple, intuitive expression for low-dose metabolized fraction f*{sub m} of any applied multiroute dose, allowing route-to-route extrapolation regardless of compound in low-dose contexts that typically are of interest in environmental VOC risk assessment. Section 2.2 of Chiu and White's paper (''Generalization to Time-Varying Exposures'') concludes that, under conditions of virtually linear metabolism, PBPK system ''solutions to steady-state exposures are directly applicable to intermittent exposures''--i.e., under such conditions, all steady-state system solutions (or output states) become valid when each dynamic input is replaced by its corresponding time-weighted average value. This conclusion, a well known axiom of linear systems theory, was stated explicitly to apply to f*{sub m} in an earlier study. A subsequent study addressed how generic steady-state PBPK solutions can be modified to estimate transient peak target-tissue concentrations at dynamic equilibrium, for dynamic exposure scenarios that involve exposure to a regular (e.g., daily) series of brief inputs by multiple pathways--an issue that may be importance for endpoints that have a cytotoxic mechanism of action.« less
  • Radiation risks at low doses remain a hotly debated topic. Recent experimental advances in our understanding of effects occurring in the progeny of irradiated cells, and/or the non-irradiated neighbors of irradiated cells, i.e., non-targeted effects associated with exposure to ionizing radiation, have influenced this debate. The goal of this document is to summarize the current status of this debate and speculate on the potential impact of non-targeted effects on radiation risk assessment and the radiation dose response profile.
  • The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis), which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism, because a high proportion of all chemicals tested are indeed rodent carcinogens. We conclude that at the low doses of most human exposures, where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed. The toxicological significance of exposures to synthetic chemicals is examined in the context of exposures tomore » naturally occurring chemicals. We calculate that 99.99% of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. The toxicology of synthetic chemicals is compared to that of natural chemicals, which represent the vast bulk of the chemicals to which humans are exposed. It is argued that animals have a broad array of inducible general defenses to combat the changing array of toxic chemicals in plant food (nature's pesticides) and that these defenses are effective against both natural and synthetic toxins. Synthetic toxins such as dioxin are compared to natural chemicals, such as indole carbinol and ethanol. The finding that in high-dose tests, a high proportion of both natural and synthetic chemicals are carcinogens, mutagens, teratogens, and clastogens (30-50% for each group) undermines current regulatory effects based on these tests to protect public health from low doses of synthetic chemicals.« less