TABLE 3

Challenges in endocrine/metabolic disruption of glucose homeostasis

Challenges related to the chemicals
 Number of structurally diverse compounds to which humans are exposed
 Measurement of chemicals in metabolically-relevant tissues
 Lack of clear structure-function relationships
  Multiple mechanisms of action for a single chemical
  Effects mediated by a chemical’s metabolites
   Chemical breakdown differing by route of exposure
  Interactions among chemicals
   Additive, antagonistic, and synergistic effects
  Interactions between chemicals and endogenous metabolites
 Persistence of chemicals
 Ubiquity of exposure to some chemicals
Challenges related to exposed individuals
 Interindividual genetic susceptibility to EDCs
  Differences in EDC target genes
  Differences in genes regulating EDC metabolism
 Coexisting diabetes risk factors
  Obesity, high-fat diet, sedentary lifestyle, family history
 Medical comorbidities
 Pharmaceutical agents/medications
 Hormonal status
  Women versus men
  Prepubertal versus reproductive age versus postmenopausal
  Eugonadal versus hypogonadal
Challenges related to experimental design and approaches
 Cross-sectional versus longitudinal epidemiological design
 Single chemical approaches versus analyses of mixtures
  Additive, antagonistic, and synergistic effects
 Nonmonotonic dose-response relationships
 Failure of cell culture or animal models to recapitulate human physiology
 Background hormonal milieu of experimental animals
 Effect of timing of exposure
  in utero or early postnatal versus adult exposure
 Transgenerational effects
 Phytochemical content of animal feed