Role of Risk Assessment in Pesticide Discovery and Development

Transcription

1 Role of Risk Assessment in Pesticide Discovery and Development Dr. Philip W. Lee Department of Applied Chemistry College of Science China Agricultural University Beijing, China Chinese Name: English Name: Home Town: Address Company Philip W. Lee Newark, Delaware, USA DuPont Crop Protection, Stine-Haskell Research Center, Newark, Delaware, USA (retired, August 2008, after 30 years of services) Degrees: BS Chemistry (University of California-Davis, 1971) MS Entomology (University of California-Riverside, 1975) Ph.D. Insecticide Toxicology (University of California-Riverside, 1976 Research Interests: Activities in China 李文华 Post Doc Drug metabolism, Vanderbilt University School of Medicine, Nashville, TN. Discovery, development and registration of pesticides Metabolism, environmental chemistry, residue analytical chemistry and field programs, computation chemistry (database, expert systems), human and environmental risk assessment Agrochemical, industrial chemicals, animal health products and pharmaceuticals Adjunct professorships in China (China Agricultural University, Nankai University, East China University of Science and Technology) Visiting professor Chaoyang University, Taichung, Taiwan Research adviser to key pesticide research institutes in China.

2 Presentation Outline ( ) A simple look at: What is risk assessment? Risk assessment used as a regulatory tool in the global regulation of drugs, pesticides and industrial chemicals What is the work flow for risk assessment? How the risk assessment process assists the pesticide discovery process - searching for the new reduced risk pesticide?? The future: New technology opportunities in chemical categorization and classification Risk type Acute Chronic Aggregated Cumulative What is Risk Assessment (RA)?? (RA)?? Risk assessment is the study the relationship between hazard and exposure Risk = f (hazard, exposure) 風險 = f ( 危害, 暴露 ) Hazard ( 危害 ) Human (mammalian) toxicity ( ) Environmental toxicity Persistence, bioaccumulative and toxicity (PBT) Exposure ( 暴露 ) Nature of exposure (dietary, non-dietary, occupational, environmental) (,,, ) Magnitude of exposure (estimation/modeling, monitoring) ( /, )

3 Types of Hazards Associate to Chemical Exposure Human health Dietary oral Worker/occupational - oral, inhalation, dermal - Residential - oral, inhalation, dermal - Environmental/ecological / Air Soil and sediment Ground and surface water Biological systems (plants, micro-organisms, animals and aqueous organisms - both target and non-target organisms) - Major International Risk Assessment Initiatives WHO/FAO ( / ) Priority organic pollutants (POP) and pesticides (Example: DDT) Pesticide regulatory agencies (USEPA, FDA, EU, individual country) (, ( 美國 ) 食品及藥物管理局, 歐盟 ) Business and Registration decision (selection of development candidates) ( ) Food safety/trade barriers (MRL) / (MRL) Industrial chemical regulation US EPA (TSCA, HPV chemicals) (Toxic Substances Control Act.) (High Production Volume) European Chemical Agency (ECHA), OECD( ) (REACH)

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6 Risk Assessment in Pesticide Registration Both the NAFTA( ) (USA/Canada/Mexico) and EU adopted risk assessment as the main safety evaluation procedure for product registration (US more on dietary and EU more on environmental),,. Similar approaches, but use different inputs and classification criteria/scheme / Increasing importance in China due to continue pesticide contamination, food safety and trade problems,,, Risk Assessment in Pesticide Registration US EPA implements aggregated and cumulative risk assessment (organophosphates, carbamates, triazines, chloroacetanilides) opportunities for replacement chemistry (,, ( 三嗪類 ) ) Risk assessment to identify Reduced Risk Pesticide for accelerated registration by the US EPA The use of reduced risk pesticide, in comparison with generally available products, yields comparatively lower risks to human health and/or the environment

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9 Why risk assessment (safety evaluation) is critical in pesticide R&D and registration? Make good business sense be pro-active (Product Stewardship, Responsible Care) ( ) As competitive advantage (accelerate product registration, Reduced Risk Pesticide ) (, ) High cost in doing business, especially in R&D, reduce business risk of selecting wrong development candidate Transparency of the risk assessment process Core technology competency both within the industry and global regulatory agencies (ECHA is seeking ca. 500 risk assessors ) Cost of New Product Commercialization Pharmaceuticals ( 醫學製藥 ) Discovery Lead Discovery and Development Clinical Trials Target ID Target Validation Screen Development 1 and 2 Compound Screens Optimization Preclinical Studies Phase I Phase II Phase III Regulatory Agrochemicals 6 years 7.5 years 1.5 years Total = 14 years and >$800 Million USD Source: Tufts University study as reported in Chemical & Engineering News, Dec 2005 ( 農藥 ) Screen Development 1 and 2 Screens Compound Optimization MOA analysis Acute Toxicity Long-Term Toxicity Field-trials Registration Source: Phillips McDougall Study on Ag R&D, Dec years Total = 11 years and ~$200 Million USD

10 High Cost of Conducting Risk Assessment Estimated $500 Million USD spent on risk assessment related activities (2004) Estimation of 5 Billion Euro over the next 10 years on REACH

11 Components of Risk Assessment Risk Assessment Process Problem Formulation Problem formulation Exposure Assessment Hazard Assessment Hazard assessment Exposure assessment Risk assessment Risk Assessment Risk Management Finally: To develop risk management and mitigation strategy

12 Human Health Risk Assessment Related to Pesticides 1. Food and food safety Pesticide residues present inside or on the surfaces of foods MRL is not a health issue, but a trade barrier (a real problem for China) MRL 2. Home and personal use pesticides Pesticides are used in and around homes to control insects, weeds, mold, mildew, bacteria, lawn and garden pests and pets from pests such as fleas and ticks (emerging personal care and animal health care markets) 蝨 Pesticides may also be used as insect repellents which are directly applied to the skin or clothing Human Health Risk Assessment Related to Pesticides 3. Pesticides in drinking water Some pesticides that are applied to farmland or other land structures can enter the ground water or surface water systems that feed drinking water supplies, 4. Worker exposure to pesticides Pesticide applicators, vegetable and fruit pickers and others who work around pesticide

13 Information Needed in Human Health Risk Assessment 人體健康風險評估的必要資訊 Define the use of the chemical (importance of Label information) 說明化學品的用途 (標示資訊的重要性) Define toxicity potential (defined by the US EPA) 說明潛在毒性 Toxicity end points (from the EPA regulatory review) Select dose response and appropriate safety factors (PAD) (Population adjust dose) Define exposure說明暴露風險 TMRC (Theoretical Mean Residue Contribution) vs. ARC (Anticipated Residue Concentration) (Actual Residue Contribution) 理論最大殘留預估值 vs. 預期殘留濃度 (實際殘留值) Measured vs. estimated/model exposure data (developing Chinese specific exposure data) China s market basket monitoring program 測量值 vs. 估算/模仿暴露資料 Acute or chronic exposure 急性或慢性暴露 Deterministic or Probabilistic 定率模式 或 機率模式 Define risk potential 說明潛在風險 Cumulative or aggregated 累積性或聚集性 Indoxacarb and Its R-enantiomer Toxicity Data for Use in RA 美國風險評估中因得克和它的對掌異構體的毒性資料

14 Issues to be Aware of for Dietary Risk Assessment 膳食風險評估中的問題 Human risk assessment selection of the appropriate toxicity end points and residue exposure based on risk 人體風險評估 根據風險選擇合適的測試和殘留暴露 MRL affects the development/marketing of pesticide (number of crops, processed food) MRL影響了農藥的發展/市場 MRL often used as a trade barrier, rather than safety concern MRL經常被用作貿易障礙而不是基於安全的考慮 Understand cumulative risk assessment for compounds with similar mode of toxicity (OP, carbamate, chloroacetanilides, triazines,etc). Look ahead for potential new chemical group(s) to be included (pyrethroids?) 了解同一類具有相同作用機制的化合物積累性風險評估, 進而包括潛 在的新藥劑類別 Emerging global regulatory issues, (global harmonization of MRL) (整合全球管理法規問題) (全球MRL調合系統) link

15 Cumulative Risk Assessment Report 積累性風險評估報告 Cumulative risk assessment report just released by the EPA in September, 2006 Detail description of method and procedures used (500+ pages) Key summary translated into Chinese for publication in China Training and workshop proposed (US EPA and ICAMA) SOP on MRL harmonization translated to Chinese 北美自由貿易協定指導檔--基 於大田試驗資料(田間試驗)制 訂農藥最大殘留限量的指導意 見 Chinese Translation of the US EPA MRL Calculation SOP

16 Compounds Included in the Cumulative Risk Assessment (包含於累積性風險評估之藥劑) Pyrethoids?? Triazines 三嗪類 Atrazine(草脫淨) Simazine (草滅淨) Propazine(普拔根) DACT (degradate) DEA (degradate) DIA (degradate) Carbamates 氨基甲酸鹽 Aldicarb Carbaryl (加保利) Carbofuran(加保扶) Formetanate HCl (覆滅螨) Methiocarb (滅賜克) Methomyl (納乃得) Oxamyl(毆殺滅) Pirimicarb (比加普) Propoxur (安丹) Thiodicarb(硫敵克) Organophosphates 有機磷劑 Acephate (毆殺松) Azinphos-methyl (谷速松) Bensulide Chlorethoxyfos Chlorpyrifos (陶斯松) Chlorpyrifos-methyl Diazinon (大利松) Dichlorvos (DDVP) (二氯松) Dicrotophos (雙特松) Etc.. Opportunities: Looking out for replacement chemistry Example: Looking at Rice Insecticide Market 實例 稻米上使用的殺蟲劑 合成除虫菊

17 What about Environmental Risk Assessment? 環境風險評估? Tiered approaches 階梯式的 Address both Fate and Effects 注重結果和影響 Different global regulatory focus for different chemicals Human health pharmaceuticals 醫藥 Pesticides 農藥 POP 不易分解的有機化合物 Industrial chemicals 工業化學品 Allow tiered computation modeling and monitoring 承認階梯式的計算模型和監控 Emerging technology (computation or in silico chemical profiling) (電腦計算方法) to meet HPV, REACH requirements Different Levels of Environmental Risk Assessment (ERA) Methodology不同級別的風險評估方法 Complex(複雜) Simple(簡單)

18 ERA Methodology 環境風險評估方法 ERAs are generally done in Tiers, the lower tiers are relatively simple to conduct and interpret, the higher tiers are more complex. 環境風險評估一般用階梯式的方法 最底層相對容易操作和解釋 高層的 相對複雜 Tier1 Quotient method Simple, quantitative comparison of exposure (PEC) and effects (LD50, LC50, NOEC, etc.) 簡單定量的比較暴露和影響 Tier 2 Similar to Tier 1, but may include refined exposure estimates (e.g., more field environmental fate studies, scenario-specific modeling) and more extensive non-target organism testing 第二層次和第一層很相似 但是包含了很多限定的暴露評估和更多的 非目標生物體實驗 Tier 3+ Mesocosm, monitoring, landscape/regional modeling, and probabilistic approaches to both exposure and effects 小的田間試驗,監測 地形/地域性模型 Key Consideration in Environmental Risk Assessment 環境風險評估中需要考慮的關鍵事項 Analysis - ecological effects characterization (identify most sensitive targets) 分析--生態學效應描述 (界定大部份敏感標的物) Ecotoxicity data and categories (acceptable risk) 毒性數據和種類 可接受的風險 Analysis - exposure characterization 分析 暴露描述 Pesticide degradation/dissipation 農藥的分解/消散 Fate and transport studies needed 結果和轉移研究是 必要的 Approaches for evaluating exposure 評估暴露的方法 Deterministic approach (single worst case exposure) 定率模式 Probabilistic approach (likelyhood) 機率模式

19 Aquatic Organisms: Acute Effects 水生生物 急性作用 Concentration (ppm) 濃度 Toxicity Category 毒性種類 <0.1 very highly toxic 劇毒 highly toxic 高毒 >1-10 moderately toxic 中等毒性 > slightly toxic 低毒 >100 practically nontoxic 基本無毒 Defined by EPA, Taiwan regulation combine 劇毒 and 高毒 together. How to select chemicals with favorable reduced risk attributes?? 怎樣選擇具有 降低風險 屬性的化合物

20 Persistence, Bioaccumulation and Toxicity Approach (PBT) 持續性 生物蓄積性和毒性途徑 Physical chemical properties 物理化學性質 Persistence Chemical properties Toxicity VP, water solubility, pka, logp 蒸氣壓, 水溶性 Chemical reactivity 化學反應 Oxidation/reduction, tautomerism 氧化/還原 互變異性 Environmental stability 環境穩定性 Hydrolytic, photolytic, soil 水解 光解 土壤 Bioaccumulation Metabolic potentials 潛在的代謝作用 Comparative metabolism (human, animal, other organisms) 比較代謝作用 人 動物 其他生物 體 Activation and detoxification 活化作用和解毒作用 ADME (pharmcokinetics) How to Generate PBT Information?? 怎樣得到PBT資訊?? Data generation 資料產生 Tiered screening data階梯式的篩選數據 High-thru put screens 高通量篩選 In silico approach 電腦的方法 (Q)SAR (Quantitative Structure-Activity Relationship ) Knowledge based predictive systems 基於預測系統的知識 Read-across based on data generated with compound(s) that are structural related (closest neighbors) 根據結構相關 的化合物的資料進行推斷

21 Computation Tools for Compound Profiling 計算工具計算化合物結構模型 REACH Guidance Documents (REACH指引檔)

22 What is REACH? 什麼是REACH REACH is the Regulation for Registration, Evaluation, Authorization and Restriction of Chemicals. REACH是化學品登記 評估 授權 限制的規則 It implements on 1st June 2007 to improve the legislative framework on chemicals of the European Union (EU). 為了改善歐盟關於化學品的立法框架,這個規則於2007年6月1號實施 REACH places greater responsibility on industry to manage the risks that chemicals may pose to the health and the environment. REACH規則使企業有更多的責任去管理那些可能對健康和環境造成危 險的化學品 In principle REACH applies to all chemicals: not only chemicals used in industrial processes but also in our day-to-day life, for example in cleaning products, paints as well as in articles such as clothes, furniture and electrical appliances. REACH 規則基本上用於所有化學品 不僅僅是工業工程中的化 學品 也包括日常生活中的化學品 例如: (清潔用品,塗料,衣物, 家具,電子物品) Drug and pesticides (but not intermediates that are exported to EU) are excluded from REACH 藥品和農藥被排除在REACH 規則外

23 Prediction of Environmental Behaviors 預測環境行為 Key properties 主要性質 Water solubility水溶性 Vapor pressure蒸氣壓 Octanol-water partition coefficient (logp) 油水分配係數 Ionization potential (pka) UV absorption spectra紫外 吸收波長 Hydrolytic水解 Photolytic光解 Soil/sediment土壤/沉澱物 Soil adsorption土壤吸收 Chemical nature of degradation products 分解物的化學性質 Predictive tools available 可用的預測工具 QSAR literatures (Quantitative Structure-Activity Relationship) QSAR database (Bioyte) Substructure degradation database基本的分解資料庫 Reaction rules for:反應規則 Hydrolysis水解 Photolysis光解 Soil degradation 土壤分解 Animal metabolism動物代謝 Syracuse Research Corporation Prediction of Toxicological Potentials 預測潛在毒性 End Points 測試 Ecological生態學的 Mammalian哺乳動物 Predictive tools 預測工具 SRC EcoSAR (Ecological ) DEREK (Human) TopKat (Human) Multicase (Human) Simulation Plus ADMET Predictor (Pharmacology)

24 Avoid Compounds Classified as PBT and vpvb 避開分類在PBT 和 vpvb中的化合物 A substance meets the persistence criterion (P-) when: 一種物質滿足持久性標準 P-) 當 the half-life in marine water is higher than 60 days 在海水中的半衰期長於60天 the half-life in fresh- or estuarine water is higher than 40 days 在河口處河水中的半衰期長於40天 the half-life in marine sediment is higher than 180 days 在海底沉積物中的半衰期長於180天 the half-life in fresh- or estuarine water sediment is higher than 120 days 在河口處低泥中的半衰期長於120天 the half-life in soil is higher than 120 days 在土壤中半衰期長於120天 The assessment of the persistency in the environment shall be based on available half-life data collected under the adequate conditions 環境中持久性的評估將會根據適當條件下的半衰期資料來進行 Avoid Compounds Classified as PBT and vpvb 避開分類在PBT 和 vpvb中的化合物 A substance meets the bioaccumulation criterion (B-) when: 一種物質滿足生物蓄積性的標準 B), 當 The bioconcentration factor (BCF) is higher than 2,000 生物蓄積濃度因數高於2000 The assessment of bioaccumulation shall be based on measured data on bioconcentration in aquatic species 生物蓄積性評估將根據水生物種類生物蓄積性測量資料進行 Data from freshwater as well as marine water species can be used 淡水和海水的資料都可以使用

25 Avoid Compounds Classified as PBT and vpvb 避開分類在PBT 和 vpvb中的化合物 A substance meets the toxicity criterion (T-) when: 一種物質滿足毒性標準 T-): 當 The long-term no-observed effect concentration (NOEC) for marine or freshwater organisms is less than 0.01 mg/kg 長期NOEC(無顯著作用濃度) 對海生的,淡水的生物小於 0.01 mg/kg The substance is classified as carcinogenic (category 1 or 2), mutagenic (category 1 or 2), or toxic for reproduction (category 1, 2, or 3), or there is other evidence of chronic toxicity 致癌物分類中的第一類或第二類 誘導突變物質的第一類或 第二類 或者有毒複製品中的第一 第二 或第三類 或者 有其他慢性毒性的證據 IARC Classification of Carcinogens 致癌物的分類 Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. 第一類 對人類有致癌作用 Group 2A: the agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.第二類a 對人類很可能有致癌作用 Group 2B: the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.第二類b 對人類可能有致癌作用 Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. 第三類 現有證據不能對人類的致癌性進行分類 Group 4: the agent (mixture) is probably not carcinogenic to human 第四類 對人類可能是非致癌物 IARC = International Agency for Research on Cancer

26 Closing Remarks Enjoy the opportunity to visit Taiwan and to meet with this group to build new connections 很高興有機會拜訪臺灣並和貴協會建立新的聯繫管道 Pesticide R&D to be a real short and long term challenge for both Taiwan and China agrochemical industry 農藥產業短期和長期的研究發展不論在臺灣和中國都具挑戰性 Risk assessment becomes a core technology 風險評估成為核心技術 Looking for new opportunity to develop the risk assessment competency in Taiwan to meet future needs (risk assessment training and workshops in China) 在臺灣尋找新機會發展風險評估以滿足將來的需求 (在中國舉行 風險評估訓練和研討會) Questions and Open Discussion (問題和討論) Questions and Open Discussion (問題和討論)