title: Relevance of the 1-year dog study in assessing human health risks for registration of pesticides. An update to include pesticides registered in Japan.
abstract: Over 400 active pesticides are registered in Japan (FAMIC 2013). The results of dog toxicity studies (usually, the 1-year study) were used by the Japanese regulatory authorities to establish the acceptable daily intake (ADI) for 45 pesticide active ingredients (about 9%). A retrospective review of ADIs established in Japan with dog studies as pivotal data for their derivation was performed: the ADIs were reassessed under the assumption that the 1-year dog study would not be available and an alternate ADI was derived based on the remaining toxicology database. In 35 of the 45 cases (77.8%) the ADI resulting from the absence of the 1-year dog study was no greater than twice the Japanese ADI, a difference considered not to be of biological significance. In 6 cases (13%) the resulting ADI was 2-5 times higher, which is considered of questionable biological relevance. On further evaluation of the database, three of these six cases were assessed as to clarify that there is no clear difference and for the other three additional studies to clarify that uncertain findings would have been required. In 3 of the 45 cases (7%) there may be a real difference within the ADI ratio of 2-5. Only in 1 case (2.2%) ADI was five times higher than that has been set. Accordingly, the absence of a 1-year dog study does not appear to influence the ADI derivation in a relevant manner in more than 98% of cases. For the four compounds with a real difference in ADI, consumer exposure would still be well below the alternative ADI. Therefore, a strong case can be made that the standard mandatory requirement to conduct a 1-year dog study, in addition to the 3-month study, is not justified and of no additional value in protecting human health. In addition, a substantial reduction in test animals could be achieved.
authors.affiliation: ToxAdvice GmbH , Reinach BL , Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Kobel
authors.forename: Ivana
authors.initials: I
authors.lastname: Fegert
authors.forename: Richard
authors.initials: R
authors.lastname: Billington
authors.forename: Richard
authors.initials: R
authors.lastname: Lewis
authors.forename: Karin
authors.initials: K
authors.lastname: Bentley
authors.forename: Carole
authors.initials: C
authors.lastname: Langrand-Lerche
authors.forename: Phil
authors.initials: P
authors.lastname: Botham
authors.forename: Masako
authors.initials: M
authors.lastname: Sato
authors.forename: Eric
authors.initials: E
authors.lastname: Debruyne
authors.forename: Christian
authors.initials: C
authors.lastname: Strupp
authors.forename: Bennard
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000818:Animals; D016208:Databases, Factual; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D007564:Japan; D019055:No-Observed-Adverse-Effect Level; D010575:Pesticides / Q000633:toxicity*; D018570:Risk Assessment; D018675:Toxicity Tests
chemical_list: D010575:Pesticides
keywords: Japan; dogs; pesticides; repeat-dose toxicity studies; study duration