Background: Isodecyl diphenyl phosphate (IDDP) is an organophosphate flame retardant currently on the market that is used as a replacement for phased-out polybrominated diphenyl ethers. Toxicological information on this class of chemicals is sparse. A short-term, in vivo transcriptomic study was used to assess the biological potency of IDDP.
Methods: Scientists at the Division of Translational Toxicology, National Institute of Environmental Health Sciences conducted this short-term in vivo biological potency study on IDDP in young adult male Sprague Dawley (Hsd:Sprague Dawley® SD®) rats. IDDP was formulated in corn oil and administered once daily for 4 consecutive days by gavage. IDDP was tested at six doses (0, 66, 132, 264, 527, and 1,054 mg/kg body weight [mg/kg] corresponding to 0, 0.169, 0.338, 0.675, 1.35, and 2.7 mmol/kg). On study day 4, animals were euthanized, standard toxicological measures were assessed, and the liver was assayed in gene expression studies using Affymetrix microarrays. Modeling was conducted to identify the benchmark doses (BMDs) associated with apical toxicological endpoints and transcriptional changes in the liver. A benchmark response of one standard deviation was used to model all endpoints.
Results: Several clinical pathology and organ weight measurements showed dose-related changes from which BMD values could be obtained. The effects include increased relative liver weight, decreased total thyroxine concentration, decreased serum bile salt/acid concentration, increased absolute liver weight, increased serum total cholesterol concentration, decreased serum albumin/globulin ratio, and increased serum high-density lipoprotein cholesterol concentration. The BMDs and benchmark dose lower confidence limits (BMDLs) were 39.8 (22.4), 67.0 (15.6), 72.9 (49.7), 74.6 (30.2), 89.3 (55.9), 146.2 (85.8), and 161.7 (68.1) mg/kg, respectively. Although serum cholinesterase activity was significantly decreased in all dosed groups (28%–60% decrease), beginning with 66 mg/kg (the lowest-observed-effect level), its BMD value was below the lower limit of extrapolation (<22.0 mg/kg).
No Gene Ontology biological processes had BMD median values <22.0 mg/kg. The most sensitive gene sets for which a reliable estimate of the BMD could be made were monosaccharide biosynthetic process and negative regulation of protein import into nucleus with median BMDs of 28.8 and 32.1 mg/kg and median BMDLs of 14.6 and 13.7 mg/kg, respectively. The top 10 most sensitive individual genes exhibited changes in expression at dose levels below which a reliable estimate of potency could be achieved (<22.0 mg/kg). Six of these genes were upregulated: Cidea, Ugt2b17, Cyp3a23/3a1, Cyrl1, Abcc3, and Akr7a3. Four genes, Sds, G6pc, C6, and Slc6a6, were downregulated.
Summary: Taken together, the most sensitive gene set BMD (BMDL) median and apical endpoint BMD (BMDL) values that could be reliably determined occurred at 28.8 (14.6) and 39.8 (22.4) mg/kg, respectively. The BMDs (BMDLs) could not be determined for any of the top 10 most sensitive individual genes and were estimated to be <22.0 mg/kg. Serum cholinesterase inhibition was also estimated to be <22.0 mg/kg. Future studies investigating lower doses would be helpful to obtain more accurate estimates of BMD values for the most sensitive individual genes and for cholinesterase inhibition.