Science, Hazard and Risk in the European Union: The Case of TiO 2 Exposures

Transcription

1 Science, Hazard and Risk in the European Union: The Case of TiO 2 Exposures David B. Warheit Ph.D, Chemours Company, Wilmington, Delaware USA Inhaled Particles XII Meeting, Glasgow, UK September 25, 2017

2 Brief Organization Mechanistic Science Regulatory Science

3 Chronic Inhalation Studies with TiO 2 Particles Lee et al., 1985/1986 Rats 1, 10, 50, 250 mg/m 3 pigment-grade (rutile) 6h/d-5d/wk-2 years Benign lung tumors 250 mg/m 3 Reliability Level 2 Heinrich et al., 1995 Rats and Mice P25 - single exp. Variable concs ~ 10 mg/m 3 18 h/d-5d/wk 2 years + 6 months (no addn. exp) RL-3 Benign and Malignant lung tumors Muhle 1985/1986 Rats 5 mg/m 3 pigment-grade (rutile) No tumors RL-3

4 Based upon the Results of the Lee et al., and Heinrich studies, TiO 2 was classified as a Category 2 Carcinogen (Inhalation) by the ECHA RAC

5 Mechanistic Science

6 Relevance of Particle Overload related lung tumors in Rats in Humans - Outline of Evidence Interspecies differences in lung responses of rats vs. other rodents Interspecies differences in particle kinetics of rats vs. nonhuman primates and coal miners Advanced and updated human respiratory tract retention models demonstrating particle retention patterns similar to morphometric studies in monkeys and coal miners. Differences in morphologies and locations of rat lung tumors exposed to overload concentrations of PSPs vs. human lung cancers to asbestos and cigarette smoke. Comprehensive epidemiology studies in PSP production workers and coal miners that demonstrate no correlation between lifetime working exposures and lung cancer.

7 Outline of Evidence - 1 Interspecies differences in lung responses of rats vs. other rodent species

8 Species Comparisons of Rodent Lung Responses to Inhaled Poorly-Soluble Particles Likelihood for Developing Particle Overload Alveolar Macrophage Responses (long-term) Pulmonary inflammatory Responses Degree of alveolar epithelial cell proliferation Fibroproliferative Effects Location of Retained Particles in the Lung Rat Mouse Hamster High High Low High (accumulation alveolar ducts) High (accumulation alveolar ducts) High (with more rapid clearance) High High Low High Medium to Low Low High and sustained Alveolar ducts primarily Moderate to Low Alveolar ducts primarily Low Less on alveolar ducts, faster clearance

9 Species Comparisons of Rodent Lung Responses to Inhaled Poorly-Soluble Particles Development of Particle Overload-related lung tumors Rat yes Mouse No Hamster No

10 Conceptual AOP Model of lung overload sequelae in Rats following chronic PSP exposures (ECETOC 2013)

11 Outline of Evidence - 2 Interspecies differences in particle kinetics of rats vs. nonhuman primates and coal miners

12 Comparisons of Rat Lung Responses vs. Human/Primates to Inhaled PSPs Likelihood for Developing Particle Overload Alveolar Macrophage Responses (longterm) Rat High High (accumulation alveolar ducts) Human/Primate Not determined Not extensive due to greater particle translocation to interstitium Pulmonary inflammatory Responses High Low Fibroproliferative Effects High and sustained Low Location of Retained Particles in the Lung Development of Particle Overloadrelated Lung Tumors Alveolar ducts primarily YES Interstitium primarily NO

13 Comparisons of Pulmonary Distribution Patterns and Lung Effects following long-term exposures of rats vs. Humans Nikula et al., 2001 F344 rats exposed to aerosols of diesel exhaust (DEEP) 0.35, 3.5 or 7 mg/m 3 ; Nonsmoking coal miners (2 mg/m 3 standard or < 10 mg/m 3 for mean working life of 40 years). Morphometric analysis of distribution of retained particle in the selected anatomical compartment in the lung + histopathology Rats -> 82 85% of retained particles in alveoli and alveolar ducts primarily in macrophages. Humans -> 80% of chronically inhaled particulate material retained primarily in pulmonary interstitium.

14 Higher mag. LM of rat lung section after 4-week exposure to 250 mg/m 3 TiO 2 particles. Most of the particles remain in alveolar ducts

15 Light Micrograph of a human lung post-mortem demonstrating interstitial-based Coal workers Pneumoconiosis

16 Equivalent Exposure Scenario Rats vs Humans

17 RAT HUMAN High Lung Burden Rat vs. High Lung Burden Human

18 Outline of Evidence - 3 Advanced and updated human respiratory tract retention models demonstrating particle retention patterns similar to morphometric studies in monkeys and coal miners. Recent studies by Gregoratto et al. to update the ICRP Model demonstrating greater translocation of inhaled radionuclides also correlates with the morphometric studies demonstrating greater interstitial particle distribution in human lungs

19 Outline of Evidence - 4 Differences in morphologies and locations of rat lung tumors exposed to overload concentrations of PSPs vs. human lung cancers to asbestos and cigarette smoke.

20 Critical Differences between Rats and Nonhuman Primates/Humans Particle Distribution patterns for Nonhuman Primates/Humans Significant Translocation of inhaled particles to Interstitium Particle Distribution patterns for Rats Mainly Macrophage Phagocytosis within alveolar ducts and neutrophilic inflamm. greater likelihood for enhanced epithelial cell proliferation response Hyperplastic responses in Rats to high dose particle exposures Normal physiological (macrophage phagocytic) responses in Nonhuman Primates + interstitialization of particles

21 Differences between human and rat lung tumors HUMANS Lung Tumors are primarily located in bronchi/bronchioles Lung tumors following exposures to cigarette smoke or asbestos but not PSPs RATS Lung tumors occur following chronic particle overload exposures to PSPs Tumors are of alveolar origin Adaptive feature of keratinizing squamous cell response

22 Outline of Evidence - 5 Comprehensive epidemiology studies in PSP production workers including Titanium Dioxide (> 24,000 workers) and coal miners (~10 6 ) that demonstrate no correlation between lifetime working exposures and lung cancer.

23 Conclusions The most plausible conclusion that can be reached is that results from chronic particle-overload inhalation studies with PSPs in rats have no relevance for determining lung cancer risks in production workers exposed for a working lifetime to these poorly soluble particulate-types.

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25 Regulatory Science

26 ECHA RAC = Risk Assessment Committee RAC members - variable sets of expertise not specifically pulmonary The RAC does not make decisions based upon Risk Assessment Risk = Hazard x Exposure misnamed? The RAC makes decisions based upon Hazard Assessments using CLP (GHS) Should be designated the Hazard Assessment Committee? The RAC does not necessarily follow conventional Toxicology Guidelines

27 OECD Guidance on the Conduct of Chronic Inhalation Toxicity/Carcinogenicity Studies OECD # For substances likely to accumulate in the lung over time due to poor solubility or other properties, the degree of lung-overload and delay in clearance needs to be estimated based on adequately designed pre-studies; ideally a 90-day study with postexposure periods long enough to encompass at least one elimination half-time. The use of concentrations exceeding an elimination half-time of approximately 1 year due to lungoverload at the end of study is discouraged.

28 NIOSH Current Intelligence Bulletin (CIB) for TiO 2 (2011) However, exposure concentrations greater than 100 mg/m 3 are generally not considered acceptable inhalation practice today. Consequently, in a weight-of-evidence analysis, NIOSH questions the relevance of the 250 mg/m 3 dose for classifying exposure to TiO 2 as a carcinogenic hazard to workers and therefore, concludes that there are insufficient data at this time to classify TiO 2 as a potential occupational carcinogen. In addition, the Heinrich et al. inhalation study using ultrafine TiO 2 as a satellite group was not considered a guideline study by the French ANSES, as it did not conform to dose-response OECD guidelines.

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31 The Divide: Pragmatic vs. Precautionary Policies Pragmatic: Science / Risk Based Values Data/Research More data, lower uncertainty Extreme data discounted due to departure from realism (e.g., irrelevant Exposures) Promotes Teamwork & Collective Efforts The Path Across the Divide should be based on Science Precautionary: Hazard Based Penalizes Data/Research More data, more (+) findings, difficult to prove the negative Extreme data often considered relevant Can promote Distrust and Contention Key Aspects of a Meaningful Policy: Proportional Risk Based Scientific Foundation Integration of the big picture (weight of evidence)

32 Conclusions Exposures to TiO 2 Particles and other Poorly Soluble Particulates (PSPs) produce lung tumors only in rats under chronic inhalation exposure conditions of particle overload but should not be classified as Human Carcinogens by regulatory authorities. The ECHA Risk Assessment Committee should practice risk assessment when human data are available.

33 Disclosure DBW is employed by a company (Chemours) that produces and sells titanium dioxide particles.