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Methyl mercury is a potent neurotoxin that causes developmental delays in young and unborn children and has been linked to neurological and cardiovascular degeneration in adults. Methyl mercury is the basis of a state-sponsored fish advisory to limit consumption of local fish in North Carolina. This study employed methods and analytic constructs from the behavioral and social sciences to assess the determinants of subsistence fishing and to promote informed fish consumption among culturally distinct and lower income subsistence fishers in southeastern North Carolina. Formative research revealed that Native American and African American were more likely than Latino residents to know of the fish advisory, and to practice procurement and preparation strategies that are mistakenly believed to render locally caught fish safe for consumption. Fish advisories were developed for each community to promote informed fish consumption intentions among residents who consume local fish. The interventions were successful in increasing knowledge and healthy intentions among most residents. Adherence to some safe fish consumption practices were constrained by cultural and economic factors. These results demonstrate the utility of multidisciplinary approaches for assessing and reducing human exposure to methyl mercury through subsistence fish consumption.