Renal toxicity and biokinetics models after repeated uranium instillation
Résumé
Uranium kidney toxicity is well known after acute uranium intake with a threshold around 3 ^g/g of kidney.
After chronical exposure kidney toxicity is controversial even after chronical ingestion of 600 mg/l during 9
months1. The main risk of contamination for workers exposed during uranium processing is inhalation and
exposure situations can occur repeatedly.
Biokinetic model after uranium intake has been recently updated by ICRP2 to include recent data. However
most of experimental data either consider acute exposure or chronic ingestion through drinking water. To
evaluate uranium intake at the kidney level after protracted exposure, assumptions are made but no
experimental data are available to support them. The objective ofthis work is therefore to verify 1) ifuranium
biokinetic model developed from acute exposure are consistent with data obtained afterrepeated contamination
of animals, 2) ifrenal toxicity modify uranium retention and excretion 3) if nephrotoxicity threshold can be
predicted by the models?
Mice (C57BL6/J) have been exposed to different Uranium nitrate hexahydrate concentration (0.03-3 mg/kg/j)
via intranasal instillation four times a week during two weeks. Uranium in urine and in tissue has been
measured at several time points during exposure and up to 42 days post exposure. In addition the kidney
toxicity has been measured, at the same time-point, in urines using Clusterin and Kim-1 kidney biomarkers
and, confirmed by in situ kidney mRNA levels of early and late nephrotoxicity markers.
For the lower uranium concentrations, the experimental retention in kidney is well predicted by the usual
biokinetic model when accounting forthe exposure profile. However, whateverthe concentration tested under
this repeated exposure scenario, the amount ofactivity retained in kidney is lowerthan predicted by the models.
Uranium biokinetics is also modified for higher doses probably due to tissue alteration and organ dysfunction
not considered in biokinetic models. A clear nephrotoxicity is detected forthe highest concentration 3mg/kg/j
and suspected after a concentration of 1mg/kg/j.
Specified biokinetic models must be developed to take into account the possible modification of excretion and
retention due to organ toxicity.