Case studies to test: A framework for using structural, reactivity, metabolic and physicochemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments.

A process for evaluating analogs for use in SAR (Structure-Activity Relationship) assessments was previously published (Wu et al. 2010). Subsequently, this process has been updated to include a decision tree for estrogen binding (from US EPA) and flags for developmental and reproductive toxicity (DART). This paper presents the results of blinded case studies designed to test this updated framework. The results of these case studies support the conclusion that the process outlined by Wu et al. (2010) can be successfully applied to develop surrogate values for risk assessment. The read across results generated by the process were shown to be protective when compared to the actual toxicity data. Successful application of the approach requires significant expertise as well as discipline to not overstep the boundaries of the defined analogs and the rating system. The end result of this rigor can be the inability to read across all endpoints for all chemicals resulting in data gaps that cannot be filled using read across, however, this reflects the current state of the science and is preferable to making non-protective decisions. Future work will be targeted towards expanding read across capabilities. Two examples of a broader category approach are also shown.

[1]  W. Krasavage,et al.  Dimethyl terephthalate (DMT): acute toxicity, subacute feeding and inhalation studies in male rats. , 1973, American Industrial Hygiene Association journal.

[2]  J. Popp,et al.  Dinitrotoluene isomer-specific hepatocarcinogenesis in F344 rats. , 1987, Journal of the National Cancer Institute.

[3]  U. Gundert-Remy,et al.  Exposure-triggered reproductive toxicity testing under the REACH legislation: a proposal to define significant/relevant exposure. , 2008, Toxicology letters.

[4]  I. Gaunt,et al.  Short-term toxicity of methyl amyl ketone in rats. , 1972, Food and cosmetics toxicology.

[5]  Karen Blackburn,et al.  A framework for using structural, reactivity, metabolic and physicochemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments. , 2010, Regulatory toxicology and pharmacology : RTP.

[6]  D. Stump,et al.  Developmental toxicity and uterotrophic studies with di-2-ethylhexyl terephthalate. , 2007, Birth defects research. Part B, Developmental and reproductive toxicology.

[7]  C. W. Tabor,et al.  Pharmacology of spermine and spermidine; some effects on animals and bacteria. , 1956, The Journal of pharmacology and experimental therapeutics.

[8]  A G Renwick,et al.  Structure-based thresholds of toxicological concern--guidance for application to substances present at low levels in the diet. , 2005, Toxicology and applied pharmacology.

[9]  S. Dyer,et al.  Human health risk assessment of long chain alcohols. , 2009, Ecotoxicology and environmental safety.

[10]  R E Chapin,et al.  Reproductive assessment by continuous breeding: evolving study design and summaries of ninety studies. , 1997, Environmental health perspectives.

[11]  L. Persson,et al.  Effects of 1,3-diaminopropane on testosterone induced hypertrophy and polyamine synthesis in mouse kidney. , 1979, Acta physiologica Scandinavica.

[12]  J. Dunnick.  NTP Technical report on the toxicity studies of ortho-, meta-, and para- Nitrotoluenes (CAS Nos. 88-72-2, 99-08-1, 99-99-0) Administered in Dosed Feed to F344/N Rats And B6C3F1 Mice. , 1992, Toxicity report series.

[13]  Oishi Hisae,et al.  Toxicity of several phosphoric acid esters in rats , 1982 .

[14]  Butyl Benzyl Phthalate.  Concise International Chemical Assessment Document 17 , 1999 .

[15]  M. Nakaichi,et al.  Embryotoxic effects of ethylene glycol monomethyl ether in mice. , 1981, Toxicology.

[16]  A two-generation reproductive toxicity study of 4-nitrotoluene in rats. , 2005, The Journal of toxicological sciences.

[17]  G Würtzen,et al.  Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing. , 2000, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[18]  A. Takagi,et al.  Chronic Oral Toxicity of a Synthetic Antioxidant, 2,2′‐Methylenebis(4‐ethyl‐6‐tert‐butylphenol), in Rats , 1996, Journal of applied toxicology : JAT.

[19]  V. Mersch-Sundermann,et al.  Cytotoxicity and genotoxicity in human lung epithelial A549 cells caused by airborne volatile organic compounds emitted from pine wood and oriented strand boards. , 2010, Toxicology letters.

[20]  Georg Karlaganis,et al.  SIDS Initial Assessment Report For SIAM 14 , 2002 .

[21]  James L. Schardein,et al.  Chemically Induced Birth Defects , 1985 .

[22]  J. Saurat,et al.  A safety assessment of branched chain saturated alcohols when used as fragrance ingredients. , 2010, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[23]  J. Hellwig,et al.  Differential prenatal toxicity of one straight-chain and five branched-chain primary alcohols in rats. , 1997, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[24]  J. Deyo.  Carcinogenicity and chronic toxicity of di-2-ethylhexyl terephthalate (DEHT) following a 2-year dietary exposure in Fischer 344 rats. , 2008, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[25]  B. Hendrickx,et al.  SIDS Initial Assessment Report , 2006 .

[26]  Q Xie,et al.  Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens. , 2001, Chemical research in toxicology.

[27]  M. Shelby.  NTP-CERHR monograph on the potential human reproductive and developmental effects of bisphenol A. , 2008, NTP CERHR MON.

[28]  L. Hastings,et al.  1,3-dinitrobenzene: toxic effects in vivo and in vitro. , 1981, Journal of toxicology and environmental health.

[29]  D. Stump,et al.  Two-generation reproduction study of di-2-ethylhexyl terephthalate in Crl:CD rats. , 2007, Birth defects research. Part B, Developmental and reproductive toxicology.

[30]  M. Gumbmann,et al.  Short-term toxicity studies of rats fed triethyl phosphate in the diet , 1968 .

[31]  R. Irwin.  NTP Technical Report on the comparative toxicity studies of allyl acetate (CAS No. 591-87-7), allyl alcohol (CAS No. 107-18-6) and acrolein (CAS No. 107-02-8) administered by gavage to F344/N rats and B6C3F1 mice. , 2006, Toxicity report series.

[32]  R. Hood,et al.  Ornithine decarboxylase inhibitors and fetal growth retardation in mice. , 1983, Teratology.

[33]  Kathleen N. Smith,et al.  Evaluation of 60 chemicals in a preliminary developmental toxicity test. , 1987, Teratogenesis, carcinogenesis, and mutagenesis.