Science, Hazard and Risk in the European Union: The Case of TiO2 Exposures
David B. Warheit Ph.D, Chemours Company,
Wilmington, Delaware USA
Inhaled Particles XII Meeting, Glasgow, UK
September 25, 2017
Brief Organization
Mechanistic Science
Regulatory Science
Chronic Inhalation Studies with TiO2 Particles
Lee et al., 1985/1986 Rats 1, 10, 50, 250 mg/m3 pigment-grade (rutile) 6h/d-5d/wk-2 years Benign lung tumors only @ 250 mg/m3
Reliability Level 2
Heinrich et al., 1995 Rats and Mice P25 - single exp. Variable concs ~ 10 mg/m3
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/m3 pigment-grade (rutile) No tumors RL-3
Based upon the Results of the Lee et al., and Heinrich studies, TiO2 was classified as a Category 2 Carcinogen
(Inhalation) by the ECHA RAC
Mechanistic Science
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.
Outline of Evidence - 1
Interspecies differences in lung responses of rats vs. other rodent species
Species Comparisons of Rodent Lung Responses to Inhaled Poorly-Soluble Particles
Rat Mouse Hamster
Likelihood for Developing Particle Overload
High High Low
Alveolar Macrophage Responses (long-term)
High (accumulation alveolar ducts)
High (accumulation alveolar ducts)
High (with more rapid
clearance)
Pulmonary inflammatory Responses
High High Low
Degree of alveolar epithelial cell proliferation
High Medium to Low Low
Fibroproliferative Effects High and sustained
Moderate to Low Low
Location of Retained Particles in the Lung
Alveolar ducts primarily
Alveolar ducts primarily
Less on alveolar ducts, faster clearance
Species Comparisons of Rodent Lung Responses to Inhaled Poorly-Soluble Particles
Development of Particle Overload-related lung tumors
Rat yes
Mouse No
Hamster No
Conceptual AOP Model of lung overload sequelae in Rats following chronic PSP exposures (ECETOC 2013)
Outline of Evidence - 2
Interspecies differences in particle kinetics of rats vs. nonhuman primates and coal miners
Comparisons of Rat Lung Responses vs. Human/Primates to Inhaled PSPs
Rat Human/Primate
Likelihood for Developing Particle Overload
High Not determined
Alveolar Macrophage Responses (long-term)
High (accumulation alveolar ducts)
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
Alveolar ducts primarily
Interstitium primarily
Development of Particle Overload-related Lung Tumors
YES NO
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/m3; Nonsmoking coal miners (2 mg/m3 standard or < 10 mg/m3 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.
Higher mag. LM of rat lung section after 4-week exposure to 250 mg/m3 TiO2 particles.
Most of the particles remain in alveolar ducts
Light Micrograph of a human lung post-mortem demonstrating interstitial-based Coal workers Pneumoconiosis
Equivalent Exposure Scenario Rats vs Humans
High Lung Burden Rat vs. High Lung Burden Human
RAT HUMAN
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
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.
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
Differences between human and rat lung tumors
Lung Tumors are primarily located in bronchi/bronchioles
Lung tumors following exposures to cigarette smoke or asbestos but not PSPs
Lung tumors occur following chronic particle overload exposures to PSPs
Tumors are of alveolar origin
Adaptive feature of keratinizing squamous cell response
HUMANS
RATS
Outline of Evidence - 5
Comprehensive epidemiology studies in PSP production workers including Titanium Dioxide (> 24,000 workers) and coal miners (~106) that demonstrate no correlation between lifetime working exposures and lung cancer.
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.
Regulatory Science
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
OECD Guidance on the Conduct of Chronic Inhalation Toxicity/Carcinogenicity Studies OECD #453
135. 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 lung-overload at the end of study is discouraged.
NIOSH Current Intelligence Bulletin (CIB) for TiO2 (2011) However, exposure concentrations greater than 100 mg/m3 are
generally not considered acceptable inhalation practice today. Consequently, in a weight-of-evidence analysis, NIOSH questions the relevance of the 250 mg/m3 dose for classifying exposure to TiO2 as a carcinogenic hazard to workers and therefore, concludes that there are insufficient data at this time to classify TiO2 as a potential occupational carcinogen.
In addition, the Heinrich et al. inhalation study using ultrafine TiO2 as a satellite group was not considered a guideline study by the French ANSES, as it did not conform to dose-response OECD guidelines.
The Divide: Pragmatic vs. Precautionary Policies Pragmatic: Science / Risk Based
Precautionary: Hazard Based
The Path Across the Divide should be based on Science
Key Aspects of a Meaningful Policy:
Proportional
Risk Based
Scientific Foundation
Integration of the big picture (weight of evidence)
Penalizes Data/Research More data, more (+) findings,
difficult to prove the negative Extreme data often considered
relevant
Values Data/Research More data, lower uncertainty Extreme data discounted due to
departure from realism (e.g., irrelevant Exposures)
Can promote Distrust and Contention
Promotes Teamwork & Collective Efforts
Conclusi