National reflection on organs-on-chip for drug development: New regulatory challenges.

Organs-on-chip (OoC) are innovative and promising in vitro models, particularly in the process of developing new drugs, to improve predictivity of preclinical studies in humans. However, a lack of regulatory consensus on acceptance criteria and standards around these technologies currently hinders their adoption and implementation by end-users. A reflection has been conducted at the National Agency for Medicines and Health products safety (ANSM) in order to address this issue, which has gained momentum at the international level in recent years. If the subject of OoC is of international interest, France is also in the process of structuring an OoC network, in order to best support the emergence of this new technological innovation. Focusing on liver-on-a-chip, the authors drafted a first list of regulatory requirements to help standardize these devices and their use. Technological and biological relevance of liver-on-a-chip was also evaluated, in comparison with current in vitro and in vivo models, based on the available literature. The authors offer an analysis of the current scientific and regulatory situation, highlighting the key regulatory issues for the future.

Comparative study of the tissue distribution of equimolar repeated doses of hydroxocobalamin and cobalt chloride in the rats.

High dose of the cobalt atom is toxic for mammals. Hydroxocobalamin is considered safe due to the inclusion of the cobalt atom into the heminic moiety. The tissue distribution of cobalt following repeated doses of either hydroxocobalamin or cobalt chloride was studied in Wistar rats. In both cases, cobalt was administered in equimolar doses daily for an overall period of three weeks. Three groups were designed. In the hydroxocobalamin treated group, ten rats received hydroxocobalamin 17.5 mg by intraperitoneal route daily. In the cobalt-treated group, ten rats received cobalt chloride 3 mg i.p. daily. In the control group, six rats received a daily injection of 0.35 mL isotonic sodium chloride i.p. Cobalt concentrations were measured by Inductively Coupled Plasma Atomic Emission. Ours results showed that in rats having received either hydroxocobalamin or cobalt chloride, the tissue concentrations of cobalt were greater than those in the control group. The present study documented that in naive rats, the repeated administration of high doses of cobalt as hydroxocobalamin leads to tissue concentrations of the atom of cobalt significantly lower than those induced by equimolar doses of cobalt administered as cobalt chloride (p <0.05). We conclude that hydroxocobalamin reduced the tissue distribution of the cobalt atom in comparison with cobalt chloride.

Ecological risk assessment of the presence of pharmaceutical residues in a French national water survey.

In this study, we focused on the list of 33 chemicals that was established through a French national prioritisation strategy. Assessing the potential risks to the environment was a step-wise procedure: (i) we determined the Predicted Environmental Concentration (PEC) of all molecules measured in the national survey based on the highest recommended dose used, (ii) we used the Measured Environmental Concentration (MEC) and the Predicted No-Effect Concentration (PNEC) to establish the Risk Quotient (RQ) based on either a PEC/PNEC (estimated risk) or MEC/PNEC (real risk) ratio. The risk assessment was performed using a binary ecological classification suggesting that appreciable risk is likely (RQ⩾1). Of the 15 molecules quantified in the survey, 12 had a PEC higher than the action limit value of 0.01µg/L. According to the EU Guideline, environmental risk was estimated as likely for the following five compounds: acetaminophen (RQ=1.6), ibuprofen (RQ=600), diclofenac (RQ=15), oxazepam (RQ=2.1) and carbamazepine (RQ=3.2). Only ibuprofen was identified as posing real environmental risk based on its MEC (RQ=1.9).

Assessment of the health risks related to the presence of drug residues in water for human consumption: application to carbamazepine.

Pharmaceutical residues have been detected at low (usually ng/L) concentrations in drinking water sources. The detection of drugs in water intended for human consumption (WIHC) has raised questions of safety. In the absence of regulatory or other official guidance, water utilities are faced with a problem of which pharmaceutical residues should be monitored and the toxicological limits that should be required. In this essay, we define an approach for the assessment of health risks related to chemicals found in drinking water. We use the examples of carbamazepine and its main metabolite 10,11-epoxycarbamazepine to demonstrate our approach, which involves application of the following algorithm: (1) when there is human or animal toxicity data, a toxicity reference value (TRV) can be calculated; (2) when this is not applicable, an attempt should be made to derive the TRV using known information about the minimum therapeutic dose (MTD); and (3) when no applicable data is available, at all, a threshold of toxicological concern (TTC) should be estimated. In the case of carbamazepine, where relevant toxicological data exists, we derived a TRV, based on the known minimum therapeutic dose (MTD). For carbamazepine's metabolite 10,11-epoxycarbamazepine, there is no toxicological data, so we applied the TTC approach. Using this approach, and combining our estimates with what is known about these chemicals' margin of exposure (MOE), suggests that there is likely to be no appreciable risk to human health exposure to carbamazepine or its major metabolite, even given the inevitable uncertainties in exposure scenarios.