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- The Future of Regulatory Toxicology: Impact of the Biotechnology Revolution

Table

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TABLE 1 Current Toxicological Practice

Parameters and biomarkers evaluated

Organ and tissue damage
    Markers of function or homeostasis
        BUN, electrolytes, cell type, ECG, BSP, etc.
        Evaluation of organ and tissue growth (organ and body weights)
Markers of cell and tissue integrity
    AST, ALT, ALP, CK, troponin, etc.
Markers of damage or damage response
        Visible morphologic evidence of damage (gross- and histopathological observation)
        Host defense responses (host-defense cell infiltration, immune cell response)
Other effects
    Reproductive effects
    Mutagenesis
    Carcinogenesis
    Special functional evaluations
        Safety pharmacology, EKG, CV
        Neurological and behavioral
        Immunotoxicology
        Pulmonary
        Dermal
        Ocular

Note. From Lehman et al.(1949); Barnes and Denz (1954); Paget (1970); D’Arcy et al. (1998; ICH Nonclinical Safety Studies Guidance for Pharmaceuticals); US Food and Drug Administration (2001). AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; CK, creatine kinase.

 

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TABLE 2 Opportunities for Improved Toxicological Assessment

Opportunities

Improved biomarkers of toxicant-induced damage
    Damage-inducible markers and defense responses
    Specific markers of cell and tissue integrity and homeostasis
 "-omic" technologies for global monitoring of multiple pathways
    Molecular markers of pathological processes (e.g., cell death, host-defense cell signaling and infiltration, etc.)
 "Fingerprinting" of molecular response and pathway perturbations
 "Bridging" biomarkers that link laboratory studies to human outcomes
Influence of genetic variation on toxic response
 Metabolic polymorphisms
 Receptor and response polymorphisms
    Individual vs. population responses
    Predictions of interactions and/or susceptibility
"Humanized" laboratory models
    Human metabolic characteristics
    Human receptors and molecular targets
    Human disease models
    Short-term carcinogenesis models based on human characteristics (including in vivo genetic markers, oncogene and suppressor inactivation models)
Noninvasive pathology and functional monitoring
Bioinformatics and artificial intelligence approaches

 

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TABLE 3 Some Classes of Damage- or Agent-Inducible Genes

Cellular characteristic Damage type or inducer class Examples References

Protein structure Protein denaturation HSP70, clpB Wickner et al., 1999
DNA integrity DNA damage p53, GADD153, recA Lindahl and Wood, 1999; Offer et al., 2002
Oxidative protectants Redox balance NF-kB, GST Pinkus et al., 1996
Metal inducible Toxic metals Metallothionein Murata et al., 1999
Xenobiotic metabolism Xenobiotics CYP1A1, CYP2E1 Parkinson, 1996



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