Toxicology dose-response relationships

See also Behavioral Toxicology Dose-Response Relationship Exposure Assessment Mixtures, Toxicology and Risk Assessment Multiple Chemical Sensitivities Neurotoxicity Pollution, Air Indoor Psychological Indices of Toxicity Respiratory Tract Sensory Organs. 

See also Androgens Developmental Toxicology Dose-Response Relationship Endocrine System Levels of Effect In Toxicological Assessment Neurotoxicity Radiation Toxicology, Ionizing and Nonionizing Reproductive System, Female Reproductive System, Male Risk... 

Natural and synthetic chemicals affect every phase of our daily Hves ia both good and noxious manners. The noxious effects of certain substances have been appreciated siace the time of the ancient Greeks. However, it was not until the sixteenth century that certain principles of toxicology became formulated as a result of the thoughts of Philippus Aureolus Theophrastus Bombastus von Hohenheim-Paracelsus (1493—1541). Among a variety of other achievements, he embodied the basis for contemporary appreciation of dose—response relationships ia his often paraphrased dictum "Only the dose makes a poison."... 

Dose—Response Relationships and Their Toxicological Significance... 

Dose-response relationship 1 he toxicological concept that the toxicity of a substance depends not only on its toxic properties, but also on the amount of exposure or dose. 

Generally, in vivo nonclinical studies should be designed to include a sufficient number of animals per group to permit a valid estimation of a drug s toxicologic and pharmacologic effects in terms of incidence, severity and the dose-response relationships involved (Thomas and Myers, 1998). The latter point requires, as... 

Models for determining the dose-response relationship vary based upon the type of toxicological hazard. In the dose-response for chemical carcinogens, it is frequently assumed that no threshold level of exposure (an exposure below which no effects would occur) exists, and, therefore, any level of exposure leads to some finite level of risk. As a practical matter, cancer risks of below one excess cancer per million members of the population exposed (1 x 10 ), when calculated using conservative (risk exaggerating) methods, are considered to represent a reasonable certainty of no harm (Winter and Francis, 1997). 

There are many circumstances in which the only information we can develop on toxic hazards and dose-response relationships derives from experiments on laboratory animals. The example of the food additive, presented in the opening pages, is just one of many circumstances in which condition A involves animal toxicology data, and condition B involves a human population, almost always exposed at small fractions of the dose used in animals, and sometimes exposed for much larger fractions of their lifetime than the animals, and even by different routes. Extrapolations under these circumstances should cause individuals trained in the rigors of the scientific method to seek some form of psychological counsel, or, better yet, to return to the laboratory. 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

Dose-response relationship and threshold for any of the adverse toxicological effects observed in the repeated dose toxicity studies. 

For experimental studies of mixtmes, consideration is given to the possibility of changes in the physicochemical properties of the test substance during collection, storage, extraction, concentration and delivery. Chemical and toxicological interactions of the components of mixtmes may result in nonlinear dose-response relationships. 

Hemminki, K., Paasivirta, J., Kurkirinne, T. Virkki, L. (1980) Alkylation products of DNA bases by simple epoxides. Chem.-biol. Interact., 30, 259-270 Hine, C.H., Kodama, J.K., Wellington, J.S., Dunlap, M.K. Anderson H.H. (1956) The toxicology of glycidol and some glycidyl ethers. Arch. ind. Health, 14, 250-264 Hooper, K., LaDou, J., Rosenbaum, J.S. Book, S.A. (1992) Regulation of priority carcinogens and reproductive or developmental toxicants. Am. J. ind. Med., 22, 793-808 Hussain, S. (1984) Dose-response relationships for mutations induced in E. coli by some model compounds. Hereditas, 101, 57-68... 

Kitchin KT, Brown JL. 1994. Dose-response relationship for rat liver DNA damage caused by 49 rodent carcinogens. Toxicology 88 31-49. 

The dose-response relationship, which reflects the fact that toxicity is a relative phenomenon, was recognized by Paracelsus and is central to toxicology. 

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