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