SAFER: State Alliance for Federal Reform of Chemicals Policy

1. SAFER: State Alliance for Federal Reform of Chemicals Policy  Ted Schettler MD, MPH Science and Environmental Health Network AAIDD teleconference June, 2007

2. This diagram serves as a unifying framework for several important concepts we�ll be discussing today. First let�s consider the etiologies of these disorders. As shown in the diagram, multiple causes interact in complex ways during windows of vulnerability to affect development. These causes include nutrition and chemical exposures during vulnerable periods in early life, genetic factors (which should not be viewed in isolation), and the social environment. While research typically focuses on one domain at time, it is increasingly recognized that complex interactions are most important. For example, several genes have been identified that influence susceptibility to environmental chemicals, including genes that affect lead absorption and metabolism (such as the vitamin D receptor and delta aminolevulenic acid dehydratase genes) (1-9), and genes that affect the metabolism of and susceptibility to organophosphate (OP) pesticides (such as the paroxonase and acetylcholinesterase genes). (10-13) Among the multiple causes of disability, chemical exposures deserve special scrutiny because they are preventable causes of harm. We turn our attention next to the developmental outcomes that result from interacting genetic, toxicologic, nutritional, and social influences. These outcomes, as shown at the right and bottom in the diagram, can be viewed as continuous traits, or as categorical diagnoses. 1. Smith CM, Wang X, Hu H, et al. A polymorphism in the delta-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect 103(3):248-253, 1995. 2. Bergdahl IA, Grubb A, Schutz A, et al. Lead binding to delta-aminolevulinic acid dehydratase in human erythrocytes. Pharmacology and Toxicology 81(4):153-158, 1997. 3. Wetmur JG. Influence of the common human delta-aminolevulinic acid dehydratase polymorphism on lead body burden. Environ Health Perspect 102 suppl 3:215-219, 1994. 4. Wetmur JG, Lehnert G, Desnick RJ. The delta-aminolevulinic acid dehydratase polymorphism higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes. Environmental Research 56(2):109-119,1991. 5. Claudio L, Lee T, Wolff MS, et al. A murine model of genetic susceptibility to lead bioaccumulation. Fundam Appl Toxicol 35(1):84-90, 1997. 6. Tomokuni K, Ichiba M, Fujisiro K. Interrelation between urinary delta-aminolevulinic acid, serum ALA, and blood lead in workers exposed to lead. Industrial Health 31(2):51-57, 1993. 7. Schwartz BS, Lee BK, Stewart W, et al. Delta-aminolevulinic acid dehydratase genotype modifiers four hour urinary lead excretion after oral administration of dimercaptosuccinic acid. Occupational and Environmental Medicine 54(4):241-246, 1997. 8. Sithisarankul P, Cadorette M, Davoli CT, et al. Plasma 5- amniolevulinic acid concentration and lead exposed children. Environmental Research 80(1):41-49,1999. 9. Sithisarankul P, Schwartz BS, Lee BK, et al. Aminolevulinic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevlinic acid, in lead-exposed workers. American Journal of Industrial Medicine 32(1):15-20, 1997. 10. Mutch E, Blain PG, Williams FM. Interindividual variations in enzymes controlling organophosphate toxicity in man. Human and Experimental Toxicology 11(2):109-116, 1992. 11. Costa LG, Li WF, Richter RJ, et al. The role of paraoxonase (PON1) in the detoxification of organophosphates and its human polymorphism. Chemico-Biological Interactions 119-120:429-38, 1999. 12. Genc S, Gurdol F, Guvene S, et al. Variations in serum cholinesterase activity in different age and sex groups. European Journal of Clinical Chemistry and Clinical Biochemistry 35(3):239-240, 1997. 13. Pilkington A, Buchanan D, Jamal GA, Gillham R, Hansen S, Kidd M, Hurley JF, Soutar CA.An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers. Occup Environ Med. 2001 Nov;58(11):702-10. This diagram serves as a unifying framework for several important concepts we�ll be discussing today. First let�s consider the etiologies of these disorders. As shown in the diagram, multiple causes interact in complex ways during windows of vulnerability to affect development. These causes include nutrition and chemical exposures during vulnerable periods in early life, genetic factors (which should not be viewed in isolation), and the social environment. While research typically focuses on one domain at time, it is increasingly recognized that complex interactions are most important. For example, several genes have been identified that influence susceptibility to environmental chemicals, including genes that affect lead absorption and metabolism (such as the vitamin D receptor and delta aminolevulenic acid dehydratase genes) (1-9), and genes that affect the metabolism of and susceptibility to organophosphate (OP) pesticides (such as the paroxonase and acetylcholinesterase genes). (10-13) Among the multiple causes of disability, chemical exposures deserve special scrutiny because they are preventable causes of harm. We turn our attention next to the developmental outcomes that result from interacting genetic, toxicologic, nutritional, and social influences. These outcomes, as shown at the right and bottom in the diagram, can be viewed as continuous traits, or as categorical diagnoses. 1. Smith CM, Wang X, Hu H, et al. A polymorphism in the delta-aminolevulinic acid dehydratase gene may modify the pharmacokinetics and toxicity of lead. Environ Health Perspect 103(3):248-253, 1995. 2. Bergdahl IA, Grubb A, Schutz A, et al. Lead binding to delta-aminolevulinic acid dehydratase in human erythrocytes. Pharmacology and Toxicology 81(4):153-158, 1997. 3. Wetmur JG. Influence of the common human delta-aminolevulinic acid dehydratase polymorphism on lead body burden. Environ Health Perspect 102 suppl 3:215-219, 1994. 4. Wetmur JG, Lehnert G, Desnick RJ. The delta-aminolevulinic acid dehydratase polymorphism higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes. Environmental Research 56(2):109-119,1991. 5. Claudio L, Lee T, Wolff MS, et al. A murine model of genetic susceptibility to lead bioaccumulation. Fundam Appl Toxicol 35(1):84-90, 1997. 6. Tomokuni K, Ichiba M, Fujisiro K. Interrelation between urinary delta-aminolevulinic acid, serum ALA, and blood lead in workers exposed to lead. Industrial Health 31(2):51-57, 1993. 7. Schwartz BS, Lee BK, Stewart W, et al. Delta-aminolevulinic acid dehydratase genotype modifiers four hour urinary lead excretion after oral administration of dimercaptosuccinic acid. Occupational and Environmental Medicine 54(4):241-246, 1997. 8. Sithisarankul P, Cadorette M, Davoli CT, et al. Plasma 5- amniolevulinic acid concentration and lead exposed children. Environmental Research 80(1):41-49,1999. 9. Sithisarankul P, Schwartz BS, Lee BK, et al. Aminolevulinic acid dehydratase genotype mediates plasma levels of the neurotoxin, 5-aminolevlinic acid, in lead-exposed workers. American Journal of Industrial Medicine 32(1):15-20, 1997. 10. Mutch E, Blain PG, Williams FM. Interindividual variations in enzymes controlling organophosphate toxicity in man. Human and Experimental Toxicology 11(2):109-116, 1992. 11. Costa LG, Li WF, Richter RJ, et al. The role of paraoxonase (PON1) in the detoxification of organophosphates and its human polymorphism. Chemico-Biological Interactions 119-120:429-38, 1999. 12. Genc S, Gurdol F, Guvene S, et al. Variations in serum cholinesterase activity in different age and sex groups. European Journal of Clinical Chemistry and Clinical Biochemistry 35(3):239-240, 1997. 13. Pilkington A, Buchanan D, Jamal GA, Gillham R, Hansen S, Kidd M, Hurley JF, Soutar CA.An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers. Occup Environ Med. 2001 Nov;58(11):702-10.

3. The developing brain Brain development begins early in fetal life and is not complete for years Brain develops under control of neurotransmitters, hormones, other endogenous chemicals susceptible to alteration by environmental factors Vulnerability extends beyond birth into adulthood

4. Cellular Events in Neurodevelopment Cell division, migration, differentiation, synapse formation, synapse pruning, and apoptosis each occur during brain development, though the timing of the sequence of events differs somewhat in various portions of the brain. The sequence is genetically programmed, but mediated by a variety of neurotrophic biochemical compounds, including neurotransmitters, and subject to disruption by environmental influences. Interference with any stage of this process may alter subsequent stages and result in permanent impairments. Neurotoxic compounds can interfere with critical processes in these events, making the developing brain uniquely susceptible to exposure. Extensive studies of a few well-known neurodevelopmental toxicants, including lead, mercury, alcohol, and nicotine, reveal multiple mechanisms by which these compounds disrupt normal brain development. These include alterations in levels of neurotransmitters or other neurotrophic compounds and impairment of cell division, migration, differentiation, synapse formation, and apoptosis. Cell division, migration, differentiation, synapse formation, synapse pruning, and apoptosis each occur during brain development, though the timing of the sequence of events differs somewhat in various portions of the brain. The sequence is genetically programmed, but mediated by a variety of neurotrophic biochemical compounds, including neurotransmitters, and subject to disruption by environmental influences. Interference with any stage of this process may alter subsequent stages and result in permanent impairments. Neurotoxic compounds can interfere with critical processes in these events, making the developing brain uniquely susceptible to exposure. Extensive studies of a few well-known neurodevelopmental toxicants, including lead, mercury, alcohol, and nicotine, reveal multiple mechanisms by which these compounds disrupt normal brain development. These include alterations in levels of neurotransmitters or other neurotrophic compounds and impairment of cell division, migration, differentiation, synapse formation, and apoptosis.

6. Well-known neurodevelopmental toxicants Alcohol � hyperactivity, cognitive deficits Nicotine � IQ deficit, learning and attention deficits Lead � impaired IQ, learning, attention; hyperactivity, impulsiveness, aggression; failure to complete school, trouble with the law

7. Well-known neurodevelopmental toxicants Mercury�Impairments of motor skills, attention, visual spatial skills, language, memory PCBs�hyperactivity, memory and attention deficits, diminished full scale and verbal IQ (in childhood and pre- teens after fetal exposure)

8. Additional chemicals of concern Brominated flame retardants Pesticides Solvents�toluene, others Manganese (soy milk, gasoline additive; DW levels over 300 ppb associated with lower WISC score; rodent and primate studies) Arsenic (DW levels above 10 ppb associated with lower WISC score) (Wasserman EHP, 2004) Fluoride Bisphenol A (interferes with thyroid hormone function) Perchlorate Many other neurotoxicants

10. Chemical regulatory policies US�Toxic Substances Control Act (EPA); Federal Insecticide Fungicide Rodenticide Act (EPA, pesticides); pharmaceuticals (FDA) EU�REACH Thanks to Richard Denison for recent report comparing policies; Environmental Defense

11. Current policies Current policy in the US based on presumption of safety (non-pesticide; non-pharmaceutical) In the US, tens of thousands of chemicals were grandfathered in when TSCA was enacted Burden of proof is on the government to show that exposures or threats of harm are sufficient to trigger safety testing or restriction.

12. Implications of current US policy Rewards ignorance; discourages development of more safety data Government must have evidence of significant exposure or harm in order to require more safety information or to regulate the chemical otherwise �unreasonable risk� requirement�including economic analysis; least onerous controls Impedes efforts to identify safer alternatives; rewards the status quo (ignorance and use patterns)

13. REACH�EU Registration, evaluation, authorization of chemicals Has just begun phase in; time will tell how effective Knowledge-driven Shifts burden of proof to manufacturers for providing basis for concluding �reasonable assurance of safety�; risk management

14. REACH Requires base sets of production, use, hazard and, in some cases, exposure data for registration. For chemicals identified as substances of very high concern, allow only those uses that are explicitly authorized.

15. REACH Two sets of specific criteria: Two sets of specific . Classification criteria for identifying dangerous substances, covering chemical, health, and ecosystem endpoints Criteria to identify substances of very high concern CMRs, PBTs, vPvB Requires registration early in the process Requires more information; prioritize chemicals for Evaluation, Authorization or Restriction

16. REACH�registration Registration: 4 tiers of data requirements: <10, 10-100, 100-1000, >1000 tonnes/yr Different data requirements in each tier All producers of a chemical must register it (can do so collectively) r Unlike TSCA no govt. review before manufacture starts (or rises to next tier)

17. REACH At the time of registration, REACH requires all manufacturers to submit available information and to generate (or propose to generate) and submit new information specified under the applicable registration requirements.

18. REACH New chemical assessments conducted by industry, not government. New chemicals may be manufactured or imported without any government review or approval of the information provided by the registrant or of the risk management measures being utilized.

19. REACH Existing chemicals: govt has the authority to assess Industry has the burden of showing that risks are adequately controlled vPvBs and PBTs are replaced with safer alternatives when they exist at an acceptable socioeconomic cost CMRs are to be replaced with safer alternatives unless registrant shows that risks are adequately controlled

20. REACH 3 classes of information Normally subject to non-disclosure unless essential to protect health and environment Always publicly available Public unless CBI claim, justified, and approved