Neurotoxicity assessment REACH

Following receipt of data the Commission drew up priority lists of substances that, on the basis of that data, were thought to have the potential to pose a risk of harm to human health or the environment. By the publication of the EU White Paper in 2001, four lists, containing a total of 141 substances, had been adopted by the relevant technical committee (CEC, 2001). The progress of these risk assessments was very slow. Risk assessment of hexabromocyclododecane (HBCD), for example, commenced in 1997 but was still not completed nine years later (ENDS, 2006). In 2006 around 16,700 tonnes of HBCD were produced every year for use as a flame retardant. It may have neurotoxic effects and interfere with the metabolism of thyroid hormone, but because risk assessment of it had not reached a conclusion there were no restrictions on its use. By 2006 final risk assessment reports were available for only about 70 substances (European Commission, 2006b) — less than 0.5 per cent of the 30,000 or so existing substances on the European market at quantities of above 1 tonne per annum. 

Seizures associated with imipenem + cilastatin have repeatedly been reported (5-7). As with other beta-lac-tam antibiotics, it is difficult to assess clearly the cause of a seizure in patients with a cluster of other predisposing factors for neurotoxicity (8) and hence to reach clear estimates of frequency. In a review of 1754 patients there was a similar incidence of seizures with imipenem -I- cilastatin as with other antibiotic regimens usually containing another beta-lactam (9). In rabbits imipenem -I- cilastatin and another carbapenems were more neurotoxic than benzylpenicillin (10). In mice, ataxia and seizures were seen, with much lower blood concentrations of imipenem than cefotaxime or benzylpenicillin (1900 pg/ml versus 3400 qg/ml and 5800 qg/ml) (11). In mice imipenem also lowered the convulsive threshold of pentetrazol (pentylenetetrazole) more than cefazolin or two other carbapenems (12). Cilastatin alone was not proconvulsant, but it increased the effects of co-adminis-tered imipenem. 

One advantage of rodents, beyond the exceptionally well-characterized immune system and availability of reagents, is the fact that DIT assessment may be able to be dovetailed into existing developmental and reproductive assessments. Certainly DIT testing using other mammalian species may be appropriate under some circumstances, but the opportunity to examine developmental immunotoxicity, developmental neurotoxicity, and reproductive toxicity using a common model suggests that the rodent is likely to remain the standard model of choice. This conclusion was also reached by various consensus panels (Holsapple et al., 2005). 

---