Heterogeneity of Toxicant Response: Sources of Human Variability

Abstract

While risk assessment models attempt to predict human risk to toxicant exposure, in many cases these models cannot account for the wide variety of human responses. This review addresses several primary sources of heterogeneity that may affect individual responses to drug or toxicant exposure. Consideration was given to genetic polymorphisms, age-related factors during development and senescence, gender differences associated with hormonal function, and preexisting diseases influenced by toxicant exposure. These selected examples demonstrate the need for additional steps in risk assessment that are needed to more accurately predict human responses to toxicants and drugs.

Regulation of Human CYP2C18 and CYP2C19 in Transgenic Mice: Influence of Castration, Testosterone, and Growth Hormone

“…Metabolism by gender-specific P450 enzymes could lead to gender-dependent susceptibility to chemical toxicants and carcinogenicity (Aldridge et al, 2003). Some reports have suggested gender differences in activity of CYP2C19 (Xie et al, 1997) and CYP2E1 (Kim and O'Shea, 1995), but such differences have been difficult to reproduce by others (Kim and O'Shea, 1995;Hägg et al, 2001;Bebia et al, 2004).…”

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“…As previously stated, the clinical relevance of the tumor and its heterogenic microenvironment is the significant contribution to the efficacy of drug therapy [2,3]. To compound the aforementioned dynamics, there is an epithelialmesenchymal transition (EMT) coefficient that influences and confounds tumor heterogeneity and hence therapeutic efficacy.…”

“…It remains one of the most challenging diseases to treat, in part, due to the heterogeneity of the malady. [1] Most cancers originate as a single cell, and thus monoclonal in origin, however, due to innate genetic instability of subsequent cell generations, new characteristics create a heterogenic disease well-defined by genetic clonal expansion epigenetic changes favoring phenotypic diversity [2]. However, cancer cells are not the only contributors to tumor heterogeneity [1].…”

“…The clinical relevance is that this tumor heterogeneity contributes significantly to the efficacy of drug therapy and therefore imparts considerable inter-individual variation in pharmacotherapy and clinical response to a myriad of medications [2,3]. Thus, this divergence underscores the necessity to personalize therapeutic regimens [3].…”

Individualizing Chemotherapy using the Anti-Diabetic Drug, Metformin, as an “Adjuvant”: An Exploratory Study

“…In part, this is due to the inherent behavior of cancer. Basic research has firmly established that cancers are highly heterogeneous, resulting in wide inter-individual variations in response to therapy [1]. This divergence underscores the necessity of personalized medicine wherein the data garnered from a person's own cancer is utilized to develop a highly individualized therapeutic regimen.…”