From dose to toxic response

Those early metallurgists who were clever enough to learn how to transform crude ores to shiny metals were prohahly also observant enough to discover that some of the materials being worked with could harm them. Some of the earliest written accounts of humans on earth provide evidence that the ancient Greeks and Romans were well aware of the poisonous properties of certain plants and metals. The case of the poisoning of Socrates with hemlock is only the most famous of the early references to the deliberate use of certain plants for suicidal or homicidal purposes. 

The science of toxicology, which we define as the study of the adverse effects of chemicals on health and of the conditions under which those effects occur, has begun to take on a well-defined shape only in the past four to five decades. The science is still struggling for a clear identity, but it has begun to find one. One of the reasons for 

All substances are poisons there is none which is not a poison. The right dose differentiates a poison and a remedy. 

A third historical strand that has helped to create modern toxicology consists of the labors of occupational physicians. Some of the earliest treatises on toxicology were written by physicians who had observed or collected information on the hazards of various jobs. The man some have called the father of the field of occupational medicine was Bernardino Ramazzini, an Italian physician whose text De Moribus Artificum Diatriba (1700) contributed enormously to our understanding of how occupational exposure to metals such as lead and mercury could be harmful to workers. Ramazzini also recognized that it was important to consider the possibility that some poisons could slowly build up in the body and that their adverse effects do not make themselves apparent for a long time after exposure begins. 

Sir Percival Pott published in 1775 the first record of occupation-ally related human cancers this London physician recognized the link between cancer of the scrotum and the occupation of chimney sweep. More of Sir Percy s work will be described in Chapter 5. 

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Toxicity shows a dose-response relationship and may range from subtle biochemical changes to lethality and may involve receptor interactions. The dose-response relation depends on certain assumptions the toxic response is a function of the concentration at the target site, the concentration at the target site is a function of dose, the toxic response is causally related to the compound. 

Figure 2 The relationship between external dose and toxic response for specific compounds. (Reproduced from Renwick AG, Dome JLCM, and Walton K (2001) Pathway-related factors The potential for human data to improve the scientific basis of risk assessment. Human and Ecological Risk Assessment 7 165-180, with permission.)...

Commercial PCBs Toxic and Biochemical Effects. PCBs and related halogenated aromatic hydrocarbons ehcit a diverse spectmm of toxic and biochemical responses in laboratory animals dependent on a number of factors including age, sex, species, and strain of the test animal and the dosing regimen (single or multiple) (27—32). In Bobwhite and Japanese quad, the LC q dose for several different commercial PCB preparations ranged from 600 to 30,000 ppm in the diet the LC q values for mink that were fed Aroclors 1242 and 1254 were 8.6 and 6.7 ppm in the diet, respectively (8,28,33). The... 

Risk characterization is tlie process of estimating tlie incidence of a healtli effect under tlie various conditions of human or animal exposure as described in the exposure assessment. It evolves from both dose exposure assessment and toxicity response assessment. The data are then combined to obtain qualitative and quantitative expression of risk. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987 Andersen and Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of... 

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