The carcinogenic risk of ingested Cr(VI) at environmentally relevant doses has been questioned(94
) on the basis of the reported high Cr(VI)-reducing capacity of gastric juice.132,133
High detoxification potential of human stomach and other tissues is also a key element of the threshold model of Cr(VI) carcinogenesis.(134
) This model would argue that despite a mutagenic mode of action, the complete detoxification of moderate Cr(VI) doses in the stomach makes it inappropriate to perform linear extrapolations of cancer risks from animal tumor responses detected at high doses that could have exceeded the capacity for gastric reduction.
The ability of gastric juices to reduce/detoxify Cr(VI) is generally accepted in the field; however, studies with human volunteers and kinetic considerations of reduction and stomach emptying time do not support the completeness of the detoxification process. Three factors influence the extent of Cr(VI) reduction in the stomach: its reduction capacity, reduction rate, and stomach emptying time. On the basis of the reported high reduction capacity of the stomach (>80 mg/day),(133
) the rate of reduction by gastric juice under fasting conditions could exhibit pseudo first-order kinetics in a broad range of low to moderate Cr(VI) concentrations. A fundamental property of first-order reactions is independence of the reaction half-time on concentration. This means that the extent of gastric reduction should be the same for both very small and very large amounts of Cr(VI). In agreement with first-order kinetics, the initial rates of reduction by human gastric juice were found to be independent of Cr(VI) concentrations.94,132
Reduction of 0.1 mg/L Cr(VI) (current EPA standard for total chromium) by artificial gastric juice was the first-order reaction.(135
) A similar bioavailability of Cr(VI) for small and large doses further supports the first-order reaction kinetics of gastric reduction. For example, human subjects excreted 2.1% of the ingested 20 ng of Cr(VI) in the 24-h urine(18
) and 1.43% of the ingested 5 mg of Cr(VI). The latter value is my very conservative estimate calculated as 1/4th of the average 4-day excretion of 5.7% reported in the original study.(136
) Thus, the bioavailability of 20 ng and 5 mg of Cr(VI) (250,000-fold range) appears to be comparable. The approximately 10-fold higher bioavailability of ingested Cr(VI) compared to that of Cr(VI) reduced with orange juice prior to ingestion(137
) suggests that the bulk of absorbed Cr from Cr(VI) was likely a cell-permeable chromate.
A classic study by Donaldson and Barreras(18
) also performed a very important experiment on the bioavailability of 20 ng of Cr(VI) that was directly delivered into the duodenum of human subjects. In this case, 10.6% of Cr was excreted in the urine versus 2.1% for ingestion. Since the duodenal delivery used 100% Cr(VI), then the amount of Cr(VI) reaching the small intestine in their oral route experiment can be derived from the urinary excretion of 2.1% divided by 0.106 = 19.8%. For the study with the ingestion of 5 mg of Cr(VI) by human volunteers,(136
) the same type of calculations using the estimated 1.43% urinary excretion predict 13.5% nonreduced Cr(VI) reaching the duodenum.
A second approach for the estimation of the percentage of Cr(VI) escaping stomach detoxification can be based on the considerations of the competing processes of stomach emptying and gastric reduction. Incubation with human gastric juice for 30 min at room temperature left 29.6% nonreduced Cr(VI) based on the diminished uptake by everted intestinal rings and 29.2% from a chromatographic profile (as determined by Image J).(18
) The mean value of two measurements gives a rate with t1/2
=17 min, which should be twice as fast at physiological temperature (t1/2
= 8.5 min) due to a typical increase in the reactions rates by a factor of 2 for each 10 °C increase. A review by Paustenbach et al.(138
) reported t1/2
= 7 min for the Cr(VI) reduction rate by human gastric juice at physiological temperature. A combination of t1/2
= 15.2 min for human stomach emptying (mean value from three studies with water)139−141
and a more protective rate of t1/2
= 7 min predicts that 22.2% Cr(VI) will reach the duodenum. Overall, both bioavailability and gastric reduction rate-based estimations suggest that 10–20% Cr(VI) ingested with water escapes gastric inactivation and reaches the small intestine, which is a site for its systemic absorption and a target of carcinogenic effects in mice. These estimates do not apply to the consumption of water with food, which is expected to promote Cr(VI) reduction through increased stomach residency time and delivery of additional reducers. Vitamin C-rich products are particularly beneficial for the enhancement of gastric detoxification of Cr(VI).