Appendix A

Physiologically Based Pharmakinetic Model for Assessing the Risk of Cancer Associated with Nitrate Exposure

The risk of cancer associated with exogenous nitrate exposure is related to its potential for conversion to nitrite by bacteria in the oral cavity and the gastrointestinal tract. Some proportion of the nitrite formed is assumed to participate in reactions that lead to the formation of potentially carcinogenic N-nitroso compounds. To estimate the relative contribution of nitrate-contaminated drinking water to this process, a physiologically based pharmacokinetic model is needed that can reflect several sources of nitrate exposure.

A model could be constructed that is consistent with the following physiologic processes.1 Nitrate exposure originates from exogenous sources (food and water) and from the endogenous synthesis of nitric oxide. Exogenous nitrite exposure may be ignored because

1  

Actual construction of the model was beyond the scope of the charge to the National Research Council.



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Nitrate and Nitrite in Drinking Water Appendix A Physiologically Based Pharmakinetic Model for Assessing the Risk of Cancer Associated with Nitrate Exposure The risk of cancer associated with exogenous nitrate exposure is related to its potential for conversion to nitrite by bacteria in the oral cavity and the gastrointestinal tract. Some proportion of the nitrite formed is assumed to participate in reactions that lead to the formation of potentially carcinogenic N-nitroso compounds. To estimate the relative contribution of nitrate-contaminated drinking water to this process, a physiologically based pharmacokinetic model is needed that can reflect several sources of nitrate exposure. A model could be constructed that is consistent with the following physiologic processes.1 Nitrate exposure originates from exogenous sources (food and water) and from the endogenous synthesis of nitric oxide. Exogenous nitrite exposure may be ignored because 1   Actual construction of the model was beyond the scope of the charge to the National Research Council.

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Nitrate and Nitrite in Drinking Water it makes a negligible incremental contribution to total exposure. Nitrate from all sources is mixed in extracellular body water. Losses and removal occur as a result of urinary excretion of nitrate and by conversion to reduced or reactive forms that are ultimately lost in feces. The half-life for clearance of nitrate from blood is about 5 hours, and the fraction lost by urinary excretion is 30-50%. An important component of human physiology is the ability of salivary glands to transport nitrate from blood into saliva. The process is either absent or diminished in all nonhuman species studied; only humans have the capacity to introduce substantial amounts of nitrite into an acidic stomach. (The optimal pH for nitrosation is 2.5-3.3.) Several considerations should be included in model development: Endogenous nitrate synthesis in the absence of infection or inflammation is constant over 24 hours. Intake of exogenous nitrate from food and water occurs as a bolus. Nitrate exposure from food is accompanied by exposure to antioxidants that inhibit N-nitrosation in the stomach. Estimating human cancer risk associated with nitrate in drinking water requires a physiologically based pharmacokinetic model that could be used to compute the relative input of nitrate from all sources, rates of input, and potential for N-nitroso compound formation. Data adequate to develop such a model are available.