A European pharmaceutical company initiative challenging the regulatory requirement for acute toxicity studies in pharmaceutical drug development

Existing approaches incorporating replacement, reduction and refinement of animal testing: applicability in food and feed risk assessment

“…Instead, information can be obtained from other studies, which are performed at more relevant doses for humans and are already an integral part of drug development. The conclusions have been discussed and agreed with representatives of regulatory bodies from the US, Japan and Europe (Robinson et al, 2008).…”

Examining the regulatory value of multi-route mammalian acute systemic toxicity studies

“…In the area of regulatory toxicology, acute toxicity studies are the longest standing class of toxicity test, dating back to the "lethal dose 50 percent" method developed by trevan (1927). However, the use of lethality as an endpoint has long been a subject of controversy on both ethical/animal welfare and scientific grounds (Balls, 1991;Robinson et al, 2008;Seidle et al, 2010). Pharmaceutical companies have stated that "these studies have limited value in terms of pre-clinical and human safety assessment compared to the substantial adverse effects experienced by some of the animals" (Robinson et al, 2008), and this sector itself has recently moved to discontinue the routine requirement for stand-alone acute toxicity studies (ICH, 2009).…”

“…However, the use of lethality as an endpoint has long been a subject of controversy on both ethical/animal welfare and scientific grounds (Balls, 1991;Robinson et al, 2008;Seidle et al, 2010). Pharmaceutical companies have stated that "these studies have limited value in terms of pre-clinical and human safety assessment compared to the substantial adverse effects experienced by some of the animals" (Robinson et al, 2008), and this sector itself has recently moved to discontinue the routine requirement for stand-alone acute toxicity studies (ICH, 2009). Systemic acute toxicity studies nonetheless remain a common feature in a number of regulatory frameworks and voluntary initiatives, such as high production volume (HPV) chemicals programs.…”

Alternative acute oral toxicity assessment under REACH based on sub-acute toxicity values

“…Prediction models based on sub-acute toxicity data or in vitro cytotoxicity tests have been suggested and developed. According to the respective authors, these models may replace in vivo acute toxicity studies partly or -in the future -in total (Creton et al, 2010;Chapman et al, 2010;Indans et al, 1998;Kinsner-Ovaskainen et al, 2013;Robinson et al, 2008;Seidle et al, 2011;Bulgheroni et al, 2009;Luechtefeld et al, 2016;Graepel et.al. 2016).…”