A strategy for structuring and reporting a read-across prediction of toxicity.

Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested.

Vitamin C plasma concentrations and leg weakness in the forelegs of growing pigs.

Four litters (41 pigs) of cross-bred pigs were studied from 6 to 26 weeks of age. Blood samples were collected at 6, 13, 21 and 26 weeks of age and analysed for contents of vitamin C, calcium (Ca), inorganic phosphorus (P) and alkaline phosphatase (ALP). The pigs were examined clinically for foreleg weakness at the ages of 21 and 26 weeks. At the age of 26 weeks the pigs were slaughtered and the right forelegs were examined macroscopically and selected samples were collected for radiological, histological and ultrastructural examination. The prevalence of foreleg lesions was high, with lesions of dyschondroplasia of the distal growth plate of the ulna in 30 pigs, synovitis of the elbow joint in 24 pigs and osteochondritis dissecans of the elbow joint in 25 pigs. At the ages of 21 and 26 weeks, five pigs had evidently crooked forelegs and 14 pigs (age 21 weeks) and 25 pigs (age 26 weeks) had mildly deformed forelegs. The serum levels of Ca, P and ALP were within normal values for growing-finishing pigs. The range of vitamin C concentrations in plasma showed a wide difference (7.1-49.8 mumol/l) but was not associated with deformed forelegs. The serum concentrations of Ca, P and ALP and the plasma concentration of vitamin C differed significantly (P = 0.05) between age groups and there was a significant (P = 0.001) positive correlation between the levels of vitamin C in plasma and the serum levels of ALP at 6 weeks of age. The aim of the present study was to determine if there was any association between the plasma levels of vitamin C and the extent of crooked or deviated forelegs in growing-finishing pigs. We could not find a vitamin C deficiency during the study and no association between low levels of vitamin C in plasma and the presence of deformed forelegs of these 40 pigs.

Hepatic activities of thiamine-dependent enzymes, glucose-6-phosphate dehydrogenase and cytochrome P4501A in Baltic salmon (Salmo salar) yolk-sac fry after thiamine treatment.

Sea-run Baltic salmon (Salmo salar) populations have been affected by the M74 syndrome since 1974 causing high yolk-sac fry losses in Swedish compensatory rearing plants. M74 has been shown to be a maternally transmitted thiamine (vitamin B(1)) deficiency. The aim of this study was to investigate possible relationships between thiamine and hepatic activities of the thiamine-dependent enzymes transketolase (TK) and alpha-ketoglutarate dehydrogenase (alpha-KGDH) in addition to glucose-6-phosphate dehydrogenase (G6PDH) and cytochrome P4501A (CYP1A), measured as 7-ethoxyresorufin O-deethylase (EROD), in Baltic salmon yolk-sac fry after treatment with thiamine. Thiamine concentrations and activities of TK, alpha-KGDH and EROD were significantly lower (P<0.05) in M74 groups compared to controls (not developing M74) and family groups of thiamine injected females. In M74-developing groups the thiamine immersions reduced the mortality from 86 to 13% and restored thiamine concentrations and activities of TK, alpha-KGDH and EROD to levels slightly lower than the immersed controls. An interesting fact was that the controls showed significantly elevated (P<0.05) TK and alpha-KGDH-activities after immersions in thiamine, indicating that they also may have a stressed thiamine metabolism. The TK and alpha-KGDH-activities of unimmersed groups correlated significantly (P<0.05) with the thiamine content. We suggest that the low activities of TK and alpha-KGDH in M74 groups may be an integrative part in the pathogenesis of M74 development.