Table 4.
Criteria used to evaluate the strength and relevance of studies included in this review.
| Abou-Donia et al. (2008) | Tanaka (2012a) | Tanaka (2012b) | Ozdemir et al. (2014) | Crosby et al. (2015) | Guideline DNT studies | ||
|---|---|---|---|---|---|---|---|
| In vivo studies Based on Adams (2010), Maurissen (2010), and EPA/OPP (2012) | Account for litter as the experimental unit for analysis | No (several pups/litter) | Yesa | Yesa | No (6 M/4 litters) | Not relevant (zebrafish) | Yes |
| Minimum 6/dose group (10 for behavior) | No (5) | Yes (10) | Yes (10) | No (4 litters) | Yes (15–18 or 30–34) | Yes (10–20) | |
| Route of administration relevant to humans | No (i.p.) | Yes (dietary) | Yes (dietary) | Yes (oral) | Unclear (immersion) | Yes (dietary) | |
| >2 dose levels | No (1 dose) | Yes (3) | Yes (3) | Yes (3) | No (2) | Yes (3) | |
| Effects at a moderate dose (limited toxicity) | Yes | Yes | Yes | No | Yes | Yes | |
| Test article characterization is adequate | Yes (∼99.5% pure) | Yes (>99.0%) | Yes (>99.0%) | No | No (purity not defined) | Yes (96% to >99%) | |
| Balance time of testing across dose levels | Nob (but small sample) | Nob | Nob | Nob | Yes | Yes |
| Kimura-Kuroda et al. (2012) | ||
| In vitro studies from: EPA (2012) | Description of test system/method | Yes |
| Test material purity/composition | Yes (>98%) | |
| Dose-concentration tested | Yes | |
| Solubility/impurities and pH | No | |
| Metabolic activation (+/−) | N.A. | |
| Appropriate negative & positive controls | Yes (nicotine) | |
| Clear description of method of analysis | Yes |
N.A., not applicable.
a
Yes for measures after weaning based on experimental design of 1 pup/sex/litter and analysis conducted on each sex separately. Prior to weaning, all pups in the litter were tested and the authors do not indicate whether the litter was the experimental unit of analysis.
b
“No” indicates the paper does not mention the observations were conducted blind or balanced across dose groups.