Nitrite-induced adrenal effects in rats and the consequences for the no-observed-effect level

In a previous subchronic oral toxicity study with potassium nitrite, hypertrophy of the adrenal zona glomerulosa was observed for all nitrite levels examined including the lowest level of 100 mg/litre. This present study was carried out, therefore, to establish a no-observed-effect level (NOEL) for nitrite. Groups of 10 male and 10 female 6-wk-old Wistar rats received KNO2 at levels of 12.5, 25, 50, 100 or 3000 mg/litre or NaNO2 at levels of 81 or 2432 mg/litre in the drinking water for 13 wk. The nitrite content of the drinking water in the latter two groups was equal to that of the 100 and 3000 mg KNO2/litre groups, respectively. Potassium and sodium concentrations were equalized in the corresponding test groups with KCl and NaCl, respectively. General health, behaviour and survival were not affected by the ingestion of nitrite. Body weight and food and liquid intake were slightly decreased in the 3000 mg KNO2/litre and 2432 mg NaNo2/litre groups for both sexes. Methaemoglobin concentration was significantly elevated in rats of both high-dose nitrite groups in wk 4 and 12, while slight increases in a number of red blood cell variables occurred with 3000 mg KNO2/litre in females in wk 12. Relative kidney weights were increased in both high-dose nitrite groups. In wk 4, plasma aldosterone and corticosterone levels were slightly decreased in males with 2432 mg NaNO2/litre and plasma corticosterone in females with 3000 mg KNO2/litre but not in wk 13. Systolic blood pressure was not affected by nitrite. Microscopic examination revealed slight hypertrophy of the adrenal zona glomerulosa in animals of the 100 and 3000 mg KNO2/litre and of the 81 and 2432 mg NaNO2/litre groups, the incidence and degree being dose related. The results obtained with 100 and 3000 mg KNO2/litre in the drinking water were comparable with those found at the same levels in the previous 90-day study. The effects with sodium nitrite were similar to those observed with potassium nitrite. The biological significance of the adrenal zona glomerulosa hypertrophy is discussed. It is concluded that the NOEL of KNO2 is 50 mg/litre in the drinking water, equivalent to about 5 mg/kg body weight/day.