Toxicant distribution

Identification of metabolic reactions at an early phase can significantly affect the drug discovery process, because bioavailability, activity, toxicity, distribution and final elimination all depend on metabolic biotransformations [1], Once obtained, this information can help researchers judge whether or not a potential candidate should be eliminated from the pipeline or modified to reduce the affinity for CYP antitarget enzymes. 

Wyman JF, Serve MP, Hobson DW, et ah Acute toxicity, distribution, and metabolism of 2,4,6-trinitrophenol (picric acid) in Fischer 344 rats. J Toxicol Environ Health 37 313-327, 1992... 

There are several physiochemical properties of the toxicant that can influence its distribution. These include lipid solubility, pKa, and molecular weight, all of which were described earlier in this chapter (Section 6.4) and will not be described here. For many toxicants, distribution from the blood to tissues is by simple diffusion down a concentration gradient, and the absorption principles described earlier also apply here. The concentration gradient will be influenced by the partition coefficient or rather the ratio of toxicant concentrations in blood and tissue. Tissue mass and blood flow will also have a significant effect on distribution. For example, a large muscle mass can result in increased distribution to muscle, while limited blood flow to fat or bone tissue can limit distribution. The ratio of blood flow to tissue mass is also a useful indicator of how well the tissue is perfused. The well perfused tissues include liver,... 

As was indicated earlier, the circulatory system and components in the blood stream are primarily responsible for the transport of toxicants to target tissues or reservoirs. Erythrocytes and lymph can play important roles in the transport of toxicants, but compared to plasma proteins, their role in toxicant distribution is relatively minor for most toxicants. Plasma protein binding can affect distribution because only the unbound... 

The lower centiles derived from the toxicity distributions of the triazine herbicides could be used to assess the relevance of environmental concentrations, especially if these concentrations are also analyzed through the use of distributional approaches (Solomon, 1996 Solomon el al., 1996). These toxicity distributions may also be used to refine monitoring and stewardship programs (Solomon, 1999 Giddings et al., 2005). 

Tier 2 PRA process involved developing environmental exposure data and chronic toxicity data distributions for individual POPs. The mean concentrations of POPs in local marine water measured at various locations were used as exposure data in the construction of the exposure distribution. The chronic toxicity data distribution was established based on published international acute toxicity data (LC50, EC50) on a variety of aquatic organisms tested in many jurisdictions, drawn primarily from the USEPA ECOTOX database (2002) (available at http //www.epa.gov/ ecotox). If the upper 5th centile of the measured chemical exposure data distribution did not exceed the lower 5th centile of its estimated chronic toxicity distribution, the potential ecological risk posed by the chemical was judged to be tolerable (Hall and Giddings, 2000). 

Fodstad, O., Olsnes, S., Pihl, A. (1976). Toxicity, distribution and elimination of the cancerostatic lectins abrin and ricin after parenteral injection into mice. Br. J. Cancer 34 418-25. Fodstad, O., Johannessen, J.V., Schjerven, L., Pihl, A. (1979). Toxicity of abrin and ricin in mice and dogs. J. Toxicol. Environ. Health 5 1073-84. 

Domingo JL, Llobet JM, Tomas JM, et al. 1986. Influence of chelating agents on the toxicity, distribution, and excretion of vanadium in mice. J AppI Toxicol 6 337-341. 

Fodstad, O., Olsnes, S. and Pihl, A. (1976) Toxicity, distribution and elimination of the cancerostatic lectins abrin and ricin after parenteral injection into mice. Br J Cancer, 34, 418 425. 

Ramsden CS, Drayson MT and Bell EB (1989). The toxicity, distribution and excretion of ricin holo-toxin in rats. Toxicology, 55, 161-171. 

A considerable effort is dedicated currently to the elucidation of the mechanisms and rates of transportation and environmental behaviour for toxic substances in general, and pesticides in particular. For this purpose various predictive models to estimate the pollutant s concentration at each environmental level are being developed. The scale of complexity ranges from very simple models, based on the extnqtolation of particular examples, followed by those taking into consideration toxic distribution between different media to reach equililMium, to very complex models including all environmental levels, including biota [10]. 

BtOchim. Biophys. Acta 218,463 (1970). Review B. Nilsson, Clin. Pharmacol. Drug Epidemiol 2, 273-277 (1979). Series of articles on pharmacology, toxicity, distribution, pharmacokinetics and clinical studies Arzncimittcl-Forsch. 33,... 

Ramsden C, Drayson M, Bell E. The toxicity, distribution, and excretion of ricin holotoxin in rats. Toxicology. 1989 55 161-171. 

---