Effect thresholds and 'adequate control' of risks: The fatal flaws in the EU council's position on authorisation within REACH.

BACKGROUND Preparation of the new European REACH (Registration, Evaluation and Authorisation of CHemicals) regulation on chemicals has reached a critical stage. Depending on how key elements of the legislative proposal are finalised, especially that on authorisation of uses of 'substances of very high concern', REACH could either provide an effective measure to drive innovation towards cleaner and safer alternatives, or instead lead to further avoidable chemical exposures on the basis of demonstrated 'adequate control' of risks. Given that some key indicators of human and wildlife reproductive health continue to decline in parts of Europe, while evidence for chemical exposure as a contributory factor grows, it will clearly be vital to get the legislation right. GOAL AND SCOPE: Whereas there is now a consensus between the European Parliament and Council of the European Union that uses of persistent, bioaccumulative and toxic (PBT) and very persistent and very bioaccumulative (vPvB) substances should only be permitted when no safer alternatives are available, major differences remain regarding the manner in which other 'substances of very high concern' (including substances which are carcinogenic, mutagenic or toxic to reproduction (CMRs) and endocrine disruptors) are addressed. This paper examines those differences in more detail and proposes some ways forward. METHODS Using case studies of specific chemicals as examples, the paper critically evaluates the concepts of 'effect thresholds' and 'adequate control' of risks, which underpin the Council's proposal for many CMRs and endocrine disruptors. RESULTS The subjectivity and uncertainties inherent in the threshold approach proposed by the Council, as illustrated by these case examples, bring its ability to ensure a high level of protection for the environment and human health into question: i. the nature and extent of toxic effects recorded depend on many different factors, including the type of test and conditions selected, the organisms exposed, the timing of exposure and precisely which effects are measured and over what timeframe. ii. doses considerably below 'no effect levels' for survival could nevertheless be causing significant impairment to health and/or reproductive success. iii. chemicals present in mixtures at levels below established thresholds for effects may, in combination, induce significant toxicological responses. DISCUSSION Under the Council's current proposal, companies will be granted authorisations for some uses of CMRs and endocrine disruptors, even if safer alternatives without these properties are already on the market. The high level of evidence required for identification of substances as being of equivalent concern represents an additional weakness in the Council approach. CONCLUSIONS Instead, a requirement (along the lines of the Parliament's proposals) to address the availability of alternatives in all cases, to use them when available and to initiate their development when not, represents a more robust, defensible and protective approach to the management of 'substances of very high concern'. The possibility for authorisation of essential uses would remain, while all avoidable uses and exposures would progressively be prevented and sustainable innovation supported. PERSPECTIVES In the long run, this can only lead to a more sustainable future for the chemical industry in Europe, as well as delivering benefits of increased protection for our environment and health for generations to come.

[1]  R. Pieters,et al.  AHTN and HHCB show weak estrogenic--but no uterotrophic activity. , 1999, Toxicology Letters.

[2]  G. Trimarchi,et al.  Oral toxicity of bis(2-ethylhexyl) phthalate during pregnancy and suckling in the Long-Evans rat. , 1998, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[3]  Christopher J. Borgert,et al.  Chemical Mixtures: An Unsolvable Riddle? , 2004 .

[4]  Harold I Zeliger,et al.  Toxic Effects of Chemical Mixtures , 2003, Archives of environmental health.

[5]  R. Altenburger,et al.  Mixture toxicity and its modeling by quantitative structure‐activity relationships , 2003, Environmental toxicology and chemistry.

[6]  B. van der Burg,et al.  In vitro and in vivo antiestrogenic effects of polycyclic musks in zebrafish. , 2004, Environmental science & technology.

[7]  Eva Jakobsson,et al.  Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[8]  Mats Tysklind,et al.  Photolytic debromination of decabromodiphenyl ether (BDE 209). , 2004, Environmental science & technology.

[9]  P. Darnerud.  Toxic effects of brominated flame retardants in man and in wildlife. , 2003, Environment international.

[10]  W. Seinen,et al.  Transcriptional Activation of Estrogen Receptor ERα and ERβ by Polycyclic Musks Is Cell Type Dependent , 2002 .

[11]  G. LeBlanc,et al.  Synergistic interaction of endocrine‐disrupting chemicals: Model development using an ecdysone receptor antagonist and a hormone synthesis inhibitor , 2004, Environmental toxicology and chemistry.

[12]  Søren Løkke,et al.  Brominated Flame Retardants: Substance Flow Analysis and Substitution Feasability Study , 1999 .

[13]  C. Steinberg,et al.  Influence of a Xenobiotic Mixture (PCB and TBT) Compared to Single Substances on Swimming Behavior or Reproduction of Daphnia magna , 2005 .

[14]  David Santillo,et al.  Playing with fire: the global threat presented by brominated flame retardants justifies urgent substitution. , 2003, Environment international.

[15]  K. Failing,et al.  Estrogenic Activity of Musk Fragrances Detected by the E-Screen Assay Using Human MCF-7 Cells , 2002, Archives of environmental contamination and toxicology.

[16]  Ulrika Fridén,et al.  Identification of the flame retardant decabromodiphenyl ethane in the environment. , 2004, Environmental science & technology.

[17]  R. S. Thomas,et al.  Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling. , 1998, Environmental health perspectives.

[18]  H. Komulainen.  Experimental cancer studies of chlorinated by-products. , 2004, Toxicology.

[19]  Søren Løkke,et al.  The Precautionary Principle and Chemicals Regulation: Past Achievements and Future Possibilities (8 pages) , 2006, Environmental science and pollution research international.

[20]  A. Kortenkamp,et al.  Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. , 2002, Environmental health perspectives.

[21]  David Santillo,et al.  The precautionary principle: Protecting against failures of scientific method and risk assessment , 1998 .

[22]  E. L I S A B E T E S I L V A,et al.  Something from “ Nothing ”-Eight Weak Estrogenic Chemicals Combined at Concentrations below NOECs Produce Significant Mixture Effects , 2022 .

[23]  Heather M Stapleton,et al.  Debromination of the flame retardant decabromodiphenyl ether by juvenile carp (Cyprinus carpio) following dietary exposure. , 2004, Environmental science & technology.

[24]  V. Valli,et al.  Subchronic oral toxicity of di-n-octyl phthalate and di(2-Ethylhexyl) phthalate in the rat. , 1997, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[25]  P. Nambiar,et al.  Immunomodulatory Effects of in Vitro Exposure to Organochlorines on T-Cell Proliferation in Marine Mammals and Mice , 2006, Journal of toxicology and environmental health. Part A.

[26]  M. Jonker,et al.  Significance testing of synergistic/antagonistic, dose level‐dependent, or dose ratio‐dependent effects in mixture dose‐response analysis , 2005, Environmental toxicology and chemistry.