Human target dose

The ABPI/BIA taskforce recommendation of basing the first human dose on the MABEL, rather than solely on the NOAEL in a toxicology species, would have led to a lower and less hazardous human starting dose. These recommendations should guide design of future preclinical safety programs and future FIH clinical protocols, particularly for products with novel targets and mechanisms and pharmacodynamics and with restricted species specificity. 

This external exposure may not necessarily correlate with internal exposure. The rate of absorption through the skin, the lung or the gastrointestinal tract determines the body burden of the chemical. Measurement of the chemical, its metabolites or products of the interaction of the chemical or its metabolites with cellular macromolecules such as proteins or DNA in body fluids and tissues determines internal exposure . Use of such biomarkers provides exact information on actual internal exposure (target dose) to an agent (Angerer et al. 2007 Boogaard 2007 Needham et al. 2007). When used in experimental studies in animals and humans they allow assessment of the individual and internal exposure as compared to external exposure. 

TSS (mg/L) Target Dose for Dose Ingested Estimated Human Oral Average % of Estimated 3... 

The data for the nerve agents are presented in Tables 3.2 and 3.3. Table 3.2 includes the TSS or estimated TSS, target dose for detection, daily human oral dose ingested, estimated human oral acute LD50, and average percent of estimated human oral acute LD50. Table 3.3 includes solubility in water, half-life in water, hydrolysis products, and chlorine resistance. 

From a theoretical standpoint, this modification represents a major advance in methods for risk assessment. The substitution of exposure values by target dose improves the quality of risk assessment by taking into account all differences between humans and the experimental species with respect to factors that influence the concentration of the toxicant at its critical target. 

Currently, human risk assessment utilising the target dose approach must be based on quantitative dose-response data generated in one or more presumed-sensitive biological models. The risk estimates developed using this approach must be carefully checked against the results of current and future human epidemiological studies. 

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