Regulating human safety: How dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options.

In the EU, one of the key determinants in the regulation and management of substances to ensure adequate protection of human health is the outcome of toxicity studies. These studies should therefore be performed in a way that the data generated are adequate to fulfil all regulatory requirements. However, in recent years, an increasing number of toxicity studies use dose levels that induce only slight, or even no toxicity, while the top dose lies well below the limit dose of 1000 mg/kg bw/d. The results of these studies have limited value for the hazard and subsequent risk assessment and risk management of substances. This paper shows why conducting toxicity studies with too low doses has severe consequences for among others classification and labelling, identification of endocrine disruptors, health impact assessment, and incident management. With this paper we aim to raise awareness on this issue and want to stress the importance of the use of sufficiently high dosing in toxicity studies. Given their central role in toxicity testing, it is therefore key to adapt where necessary the descriptions in OECD test guidelines and guidance documents on requirements for dose level setting, to make sure they are as explicit and unambiguous as possible.

Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management.

The KMD (kinetically-derived maximum dose) is an increasingly advocated concept that uses toxicokinetic data in the top dose selection for toxicity testing. Application of this concept may have serious regulatory implications though, especially in the European Union. The basic assumption is that the relationship between internal and external dose (IED) shows an inflection point where linearity transits into non-linearity due to saturation of underlying processes; top doses in toxicity tests should not be above the inflection point, provided human exposures are well below this point. A critical analysis of the KMD concept and its underlying assumptions shows, however, that the IED relationship is non-linear over the whole dose range, without any point of inflection. The KMD concept thus aims to estimate a non-existing point, rendering it invalid for use in toxicity testing. Moreover, the concept ignores the key question in toxicology: What kind of toxic effects occur at which doses? These and several other reservations against the KMD concept are discussed and illustrated with three existing applications of the KMD approach. Hence, we recommend to abolish the KMD concept for selecting top doses in toxicity testing. This requires the updating of regulations, guidance documents and OECD test guidelines.

Synthetic turf pitches with rubber granulate infill: are there health risks for people playing sports on such pitches?

The presence of carcinogenic substances in rubber granulate made from old car tyres raised concerns that the use of this granulate as infill on synthetic turf pitches may cause leukaemia and lymphoma in young football players and goalkeepers. Limitations in a number of prior studies on the topic casted doubts on their conclusion that it was safe to play sports on such pitches. Rubber granulate samples from 100 Dutch synthetic turf pitches were analysed for 45 (all samples) or 79 substances (a subset). A subset of samples was additionally analysed for migration of polycyclic aromatic hydrocarbons (PAHs), phthalates and metals into sweat and the gastrointestinal tract, and for evaporation of volatile substances into air. Exposure scenarios were developed to estimate the exposure of amateur football players via the oral, dermal and inhalation route to the most hazardous substances in rubber granulate. Risks to human health were assessed by comparing toxicological reference values for these substances with the exposure estimates. A number of carcinogenic, mutagenic and reprotoxic substances were present in rubber granulate used on Dutch pitches. No concern was, however, identified for phthalates, benzothiazoles, bisphenol A and the metals cadmium, cobalt and lead, as their exposures were below the levels associated with adverse effects on health. PAHs appeared to be the substances of highest concern, but even they present no appreciable health risk with exposures resulting in additional cancer risks at or below the negligible risk level of one in a million. Our findings for a representative number of Dutch pitches are consistent with those of prior and contemporary studies observing no elevated health risk from playing sports on synthetic turf pitches with recycled rubber granulate. Based on current evidence, there is no reason to advise people against playing sports on such pitches.

The European Union risk assessment on zinc and zinc compounds: the process and the facts.

A risk assessment on zinc and zinc compouns was carried out withn the framework of Council Regulation 793/93/EEC on Existing Chemicals. This risk assessment basically followed the European Union (EU) technical guidance documents (TGDs). These TGDs are built on the current knowledge on quantitative risk assessments, mainly for organic chemicals. This article describes the tailor-made approach for the zinc risk assessment. This work lasted almost a decade and involved the contributions of all EU member states and industry, who discussed the risk assessment during technical meetings. The risk assessment is initially based on scientific findings but is interrelated with pragmatic considerations. It follows a comprehensive approach, covering both environmental and human health. In the environmental part, new methodologies were developed to deal with the natural background of zinc, essentiality, speciation, and the use of species sensitivity distributions. The major results and the process of drawing conclusions of the risk assessment are outlined: potential environmental risks of zinc and zinc compounds may occur at local and regional scales in surfacewater, sediment, and soil. No potential health risks were identified for consumers and man indirectly exposed via the environment. For workers, potential health risks were identified only for zinc oxide and zinc chloride.