Analysis of dose/time/response relationships for chronic toxic effects: the case of acrylamide.
This case study illustrates how a very simple dynamic modeling approach can extract information of interest for both toxic mechanism research and risk assessment from a series of dose/time/response data. The technique is applicable for effects that are thought to result from damage processes that are reversible, at least at low doses and times of exposure. The data sets analyzed provided information on some specific manifestation of acrylamide neurotoxicity produced by different combinations of acrylamide dose rate and duration of exposure. Assuming that responses occur when a specific amount of axonal damage accumulates, and that the repair of damage depends directly on the amount of damage present, the dose-related change in the time required to produce a specific type of effect can be used to estimate: (1) The rate of repair of the incipient damage - and differences in repair rates for different individuals within species, and among different species, and (2) The dose of acrylamide that would be just barely able to produce each effect in each species, if the experiment were conducted over the animal's entire lifespan. Information of the first type may also be helpful in neurotoxicology research. Specific biomarkers for the main process causing a particular response should be repaired in different locations and in different species with the dynamics that are consistent with the repair rates calculated from the dose vs. time-of-effect data.
Hattis
D
D
Center for Technology, Policy and Industrial Development, Massachusetts Institute of Technology, Cambridge 02139.
Shapiro
K
K
D020106:Acrylamide; D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D003198:Computer Simulation; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D009422:Nervous System Diseases / Q000139:chemically induced; D010215:Papio; D012306:Risk; D013997:Time Factors
D000178:Acrylamides; D020106:Acrylamide