A weight-of-evidence approach for setting OELs for poorly soluble, low-toxicity nanoparticles

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1 A weight-of-evidence approach for setting OELs for poorly soluble, low-toxicity nanoparticles 25 exposure post-exposure 2 non-overload overload Lung Dose Days Jürgen Pauluhn Germany Washington, DC Sept. 1, 212 1

2 Outline Outline Principal Mode of Action of low-toxicity PSPs Pharmacokinetic model to interrelate the cumulative lung dose with associated chronic changes Verification of kinetic modelling by retrospective analysis of inhalation studies with fine and ultrafine PSPs The kinetic cornerstones of low-toxicity PSPs must be observed for designing long-term inhalation studies Derivation of Occupational Exposure Levels (OELs/ DNELs) based on a unifying rat-human overloadthreshold concept Summary and conclusions 2

3 5nm Chronic Exposure Paradigms require focus on the Chronic Mechanisms of inhaled low-toxicity PSPs The metric of dose depends on the chronic Mode of Action: Instant effect at the initial site of deposition. Transient surfactant dysfunction, coating and opsonation of PSPs. Phagocytosis of PSPs by alveolar macrophages (AM). Chemotactic stimuli for AMs and Ns to migrate into the alveoli. Any increased pool of AMs increases the lung burden and residence time of retained PSPs. OELs are designed for preventing overload-like effects to occur. Lung Burden [l resp /m³] Epithelial lining fluid Nociception Type I pneumocyte Blood capillary MoA I lung burden MoA II Interstitial clearance (-order) may contribute to total lung burden but necessarily not alveolar burden. MoA I + MoA II MoA I Lung Effects [A.U] 3

4 Putative Mechanisms of inhaled low-toxicity Nanoparticles Dissolution/ bioavailability Direct mode of action (acute) Retention-related indirect mode of action (cumulative, chronic) Surfactant dysfunction time Type II Cell activation 1 MoA I MoA II Substancespecific Lung Burden [mg Substance resp /kg rat ] Generic & particle-specific System variables: Size of AM Total number of AM Retained volume dose per AM

5 The Principal chronic Mode of Action and Lung- Overload are interrelated Low-toxicity PSPs do not show any (subcompartmental) solubility. Increasing cumulative lung burdens cause particle-displacement volumedependent increase in total lung cells (V d ). Prevailing experimental evidence suggests that the particle volume is a lead metric to understand and model the AM-mediated kinetics of PSPs. Kinetic hallmarks can differentiate adaptive from overload effects as well as particle-specific effects. TCC [#1 6 /Lung] V d Repeated Exposure Particle exposure groups Air control groups t 1/ 2 V d Cx t [mg/m³ x days] or ln(2) Vd CL 5

6 Particle Translocation to the LALNs occurs secondary to Overload-dependent Inflammation Baytubes (r:.2 g/cm³) 13-wks+26 wks postexposure LALN Burden [ng Co/Organ] Lung Associated Lymph Node Burden.1 mg/m³.4 mg/m³ 1.5 mg/m³ 6 mg/m³ N Relative Count (x to 1 Control 4 cells/lung) [%] N (% based) control 1 mg/m³ 2 mg/m³ 5 mg/m³ 1 mg/m³ * * Study Study Week Day * Magnetite (r: 4.6 g/cm³) 4-wks+26 wks postexposure LALN Particle Burden [g Fe 3 O 4 /Organ] control 1 mg/m³ 2 mg/m³ 5 mg/m³ 1 mg/m³ * * * Relative to Control [%] N (absolute) * control 1 mg/m³ 2 mg/m³ 5 mg/m³ 1 mg/m³ * As long as the overload-threshold is not exceeded, the kinetics of PSPs appears to be predominated by the AM-mediated clearance. 6

7 Volumetric Capacity of Alveolar Macrophages and Overload-Threshold (MoA II ) Rat-specific Overload threshold 4.2 l resp / kg rat 1 6 AM v6% 7 1 kg rat 1 cumulative pulmonary dose m 3 Volume-load of AM-pool 6%: no change in pool-size (= kinetic NOAEL) Generic NOAEL rat Parameterization of V d : Average AM Volume ( m³) 7. * x 1 *: empirically confirmed in the current 13-week rat inhalation study * Average AM Counts in Lung AM Volume per Lung ( m³/kg bw) Rat (kg - based) x x 1 1 Human (7 kg) x 1 11 Human-specific Total AM vol Respirability Inhaled volume Time to attain overload threshold Generic NOAEL human 7

8 Volumetric Capacity of Alveolar Macrophages and Overload-Threshold (MoA II ) Cumulative alveolar threshold volume dose: 4.2 l pulm / kg rat Constrains: AM = f(c x t); ØAM = constant Alveolar ventilation: Daily dose m³.19 kg lung ratday Chronic inhalation exposure concentration (6 h/day, 5-times/wk): pulm kg l 2 m³ kg ratday ratday.54 l m³ The kinetic threshold of -volume-dependent lung overload is the theoretical volumetric NOAEL for any poorly soluble, granular low-toxicity particulate resp 8

9 Cumulative Threshold Dose: The Transition from Homeostasis to Overload (increased V d ) 4.2 l kg rat 4.2 l lung kg rat 4.5[ g lung kg rat ] f cum 4.2 l [ day / g lung kg rat ] V L [ m³ / day] 4.2 l 4.5 f.29m³ cum f cum 1l.29m³ Daily exposure dose to attain the overload threshold: NOAEL pred f cum 1l mg r.29m³ l 1 Depos pulmonary mg [ ] m³ Starting point for dose selection for repeated inhalation exposure studies : respirable fraction of particulate matter likely to be deposited in the pulmonary region 9

10 Estimation of generic No-observed-adverse Effect Levels (NOAELs) for any PSP and Study Type 5 Daily dose to attain threshold f f f cum14wks cum13weks cum4wks Dose-Time adj Lung Burden [ l resp /kg rat ] l/day - 5 days.24 l/day - 4 week.15 l/day - 13-weeks.69 l/day - 2 yr Lung overload threshold X3.4 Not necessarily applicable to 1-wk studies since MoAI -related acute effects may confound retention-related chronic effects. Lung Burden [ l resp /kg rat ] X l/m³ - 2 yr (1% steady-state).69 l/m³ - 13 weeks (67% steady-state).69 l/m³ - 4 weeks (29% steady-state).69 l/m³ - 5 days (8% steady-state) Lung overload threshold

11 The kinetics of adaptive changes in the V d and increased Ns are interrelated Retention Half-time [days] Cumulative Volume Dose & Elimination t 1/2 Fe 3 O 4-13 wks Fe 3 O 4-2 wks Carbon Black-13 wks utio 2-13 wks AlOOH-4nm-4wks AlOOH-1nm-4wks MWCNT-13 wks ptio 2-13 wks Overload-threshold y= *(1-exp(-.8*x)) N Count [x 1 4 cells/lung] Cumulative Volume Dose & BAL-Neutrophils AlOOH-4 nm (4 wks) AlOOH-1 nm (4 wks) Fe 2 O 3 (4-wks) MWCNT (13 wks) Fe 2 O 3 (13 wks) Prediction based on overload threshold Cumulative Volume Concentration [ l resp /m³] Volume Dose [ l/lung] Cumulative Volume Concentration [ l resp /m³] Volume Dose [ l /lung] 1. Kinetic threshold (homeostasis) precedes the effect threshold (inflammation, N) 2. Any elimination t ½ > 1 year due to kinetic overload does deliver relevant information for hazard identification BAL-N [%] - Observed BAL-N 4-week study BAL-N 13-week study N 3.7% at 5 l /m³ x days (overload threshold) BAL-N [%] - Predicted 11

12 The cumulative Lung Dose, not duration, determines the terminal t 1/2 and the Study Outcome Half-time t 1/2 [days] (Fe 3 O 4 ) C x t [mg/m³ x days] Fe 3 O 4 1-week (simulated) 4-weeks (simulated) 4-weeks (empirical) 13-weeks (simulated) C x t determines the cumulative lung burden, t 1/2, and the associated intensity of effect. 2. Time-related aggravations of effect did not occur. Cytodiferentials [%] BAL-Cell Count [x1 6 ] BAL-N BMCL (95%): 4.5 l resp /m³ x days = 5.2 mg/m³ Cumulative Retained Particle Volume [l resp /m³ x days] BAL-TCC 4-week (males rats) 13-week (males and females combined) N 3.7% at 5 l /m³ x days (overload threshold) BMCL (95%): 1.1 l resp /m³ x days = 11.6 mg/m³ 4-week (males) 13-week (males and females combined) (Fe 3 O 4 ) (Fe 3 O 4 ) Cumulative Retained Particle Volume [l resp /m³ x days] 12

13 Proof-of-Principle for low Density PSPs 13-Week Rat Baytubes Inhalation Study (Pauluhn, 21) weeks Lung Burden [l resp /m³] mg MWCNT/m³ - terminal t 1/2 : 87 days.4 mg MWCNT/m³ - terminal t: 1/2 : 175 days 1.5 mg MWCNT/m³ - terminal t: 1/2 : 428 days 6 mg MWCNT/m³ - terminal t: 1/2 : 788 days Overload-Threshold MWCNT Cytodifferentials [x1 4 cells/lung] weeks Macrophages non classifiable N Lymphocytes foamy cells Concentration [mg/m³] 5 postexposure period NO( A) EL predicted 1l.29m³ mg.2 8 m³ Cytodifferentials [x1 4 cells/lung] Macrophages non classifiable N Lymphocytes foamy cells NOAEL B-BAL-N% :.16 mg/m³ (BMDL) Concentration [mg/m³] 13

14 Proof-of-Principle for high Density PSPs 13-Week Rat Magnetite Inhalation Study (Pauluhn, 212) 12 1 Lung Burden [l Fe 3 O 4 -Resp/m³] NO( A) EL predicted 1l.29m³ mg/m³ - t 1/2 = 94 days 15 mg/m³ - t 1/2 = 177 days 5 mg/m³ - t 1/2 = 392 days Overload threshold 1 mg 5 8 m³ Cytodifferentials [%] Cytodifferentials [x1 4 cells/lung] Macrophages non classifiable N Lymphocytes foamy cells Macrophages non classifiable N Lymphocytes foamy cells Concentration [mg/m³] Concentration [mg/m³] BAL-Total Cell Count measurements most sensitive to detect changes in V d (t 1/2 )

15 Proof-of-Principle for unit Density PSPs 2 Year Toner Rat Inhalation Study (Muhle, 1991) Lung Burden [ l resp /m³] Toner 1 mg/m³ - terminal t 1/2 : 82 days 4 mg/m³ - terminal t 1/2 : 29 days 16 mg/m³ - terminal t 1/2 : 68 days Overload-Threshold NOAEL f cum where: r = 1.2 g/cm³ (toner) f vi = 61 resp = 5.3% NO( A) EL 1l r.29m³ predicted i mg l 1 Depos pulmonary mg [ ] m³ 1l mg m³ m³ NO( A) EL observed i mg 1. m³ Based on BAL_N Empirical t 1/2 at 1, 4 und 16 mg/m³: 81 (75-88), 173 ( ) and 568 (36-1 days) Hypothesis verified 15 15

16 Repeated Exposure Inhalation Studies: Comparison of Predicted and empirical NOAELs 12 1 NO(A)EL observed NO(A)EL predicted r=4.6 4 wks Concentration [mg/m³] r=.2 r=1.2 2 yr r= wks r= wks 13 wks MWCNT Toner CB Fe3O4 Fe3O4 NOAEL f cum 1l r.29m³ mg l 1 Depos pulmonary mg [ ] m³ 16

17 Kinetic Modeling-based Study Design for Inhalation Testing of low-toxicity (Nano)Particles Lung Burden [ l PSP-Resp/m³] wk Study.26 l/m³ - t 1/2 = 94 days.78 l/m³ - t 1/2 = 152 days 2.6 l/m³ - t 1/2 = 327 days Lung overload threshold Lung Burden [ l PSP-Resp/m³] wk Study.11 l/m³ - t 1/2 =96 days.33 l/m³ - t 1/2 = 167 days 1.1 l/m³ - t 1/2 = 384 days Lung overload threshold l/m³ - t 1/2 = 113 days 2-yr Study (3x) 1.7 l/m³ - t 1/2 = 113 days 2-yr Study (2x) Lung Burden [ l PSP-Resp/m³] l/m³ - t 1/2 = 324 days.7 l/m³ - t 1/2 = 754 days Lung overload threshold Targeted spacing: x 1 Actual spacing: x 5 Lung Burden [ l PSP-Resp/m³] l/m³ - t 1/2 = 21 days.28 l/m³ - t 1/2 = 428 days Lung overload threshold Targeted spacing: x 2 Actual spacing: x Long-term Inhalation Studies with PSPs should not exceed the MTD (= t 1/2 >1 year) 17

18 Kinetic Modeling-based Study Design for Inhalation Testing of low-toxicity (Nano)Particles 8 5 Elimination Half-time [days] week - 3x 13-wk - 3x 2-yr - 3x 2yr - 2x MTD N in BALF [%] week - 3x 13-wk - 3x 2-yr - 3x 2yr - 2x Concentration [ul PSP respirable /m³] Concentration [ul PSP respirable /m³] Basis: V d -dependence of BAL-Ns There is an apparent dependence of BAL-N on TCC (V d ) and the cumulative volumetric particle lung burden. In the absence of any increased TCC, BAL-N% <4% appear to be toxicologically insignificant. 18

19 Volumetric Capacity of Alveolar Macrophages and Overload-Threshold (MoA II ) in Human Workers Human-specific 11 6 Overload threshold AM v6% kg human 1 3 l / kg cumulative pulmonary dose pulm human 1 m 3 Volume-load of AM-pool 6%: no change in pool-size (= kinetic NOAEL) Parameterization of V d : Average AM Volume ( m³) 7. * x 1 *: empirically confirmed in the current 13-week rat inhalation study * Average AM Counts in Lung AM Volume per Lung ( m³/kg bw) Rat (kg - based) x x 1 1 Human (7 kg) x 1 11 Respirability Inhaled volume t 1/2 should be 7-times higher due to 7-times higher V d which means t 1/2 = 42 days t 1/ 2 ln(2) Vd CL Generic NOAEL human 19

20 Volumetric Capacity of Alveolar Macrophages and Overload-Threshold (MoA II ) in Workers When accounting for the species-specific differences in the kinetic hallmarks of PSP (AM-mediated clearance only), the cumulatively retained pulmonary dose for attaining the overload-threshold is similar in rats and humans. Hence, following adjustment for ventilation and respirability, the paradigm devised for rats are also applicable to humans. 2

21 Estimation of Human Equivalent Lung Dose Rat- or Human-based (MWCNT) Ventilation rat (.8 L/kg-min) = 24 ml/min (3 g rat) x 36 min =.86 m³/day Ventilation human: 1 m³/day Ventilation x Deposition: AF Clearance: AF V F BW EA aa H lungburden A/ H VEH Fa H BWA V t ln 2 BW ln 2 BW d A 1/ 2H H clearance A/ H Vd H t1/ 2A A Parameterization of V d : Average AM Volume ( m³) 7. * x 1 *: empirically confirmed in the current 13-week rat inhalation study * Average AM Counts in Lung AM Volume per Lung ( m³/kg bw) Rat (kg - based) x x 1 1 Human (7 kg) x 1 11 per rat = 2.1 x 1 1 (3 g) per human = 3.5 x

22 5 Derivation of OEL (MWCNT): Empirical Approach Lung Burden [ l resp /kg rat ] l/day - 5 days.24 l/day - 4 week.15 l/day - 13-weeks.69 l/day - 2 yr Lung overload threshold OEL NO( A) EL A AF AF lungburden A/ H clearance A/ H AF 1 StudyDurat ion AFStudyDuration days2 years mg.92 mg OEL.16BMDL.1 ( Baytubes ) m³ m³ (chronic exposure) 22

23 OEL Calculation for MWCNT (Baytubes): Theoretical Approach OEL generic.5 l m³ respirable AF AF lungburden A/ H clearance A/ H 1 agglomerat e Generic threshold rat 6h/day-5-times/week Rat-to-human differences in lung dosimetry-kineticsexposure duration/day. Assumption: aerosol size in inhalation chamber = workplace Density of agglomerates at workplace OEL generic l.5 m³ mg.2 l mg.1 m³ (chronic exposure) Which means the theoretical mechanism-based approach verifies the empirical approach and vice versa. The NOAEL depends on kinetic factors (dosimetry) and not yet unknown Mode of Actions. 23

24 5 OEL Calculation for Fe 3 O 4 : Empirical Approach Lung Burden [ l resp /kg rat ] l/day - 5 days.24 l/day - 4 week.15 l/day - 13-weeks.69 l/day - 2 yr Lung overload threshold OEL NO( A) EL A AF AF lung burden A/ H clearance A/ H AF 1 StudyDuration mg.92 mg OEL ( 4) ³ ³ Fe O BMDL 3 m m.69 (chronic exposure based on 13 wk study & prediction) mg.92 mg OEL ( 4) ³ ³ Fe O BMDL 3 m m.69 (chronic exposure based on 4 wk study & prediction) 24

25 Summary: Computational Design of Repeated Exposure Inhalation Studies Anticipation of threshold Cxt for overload (= no-observed-adverse effect concentration, NOAEL). NOAEL, LOAEL and MTD can be rationalized based on the dynamic overload- dependent increased V d and associated t 1/2. Appropriate postexposure period can be selected to verify simulated clearance and reversibility for particles being inactivated (MoA I ). NOAEL Lung Burden [l resp /m³] f cum 1l r.29m³ mg l.1 mg MWCNT/m³ - terminal t 1/2 : 87 days.4 mg MWCNT/m³ - terminal t: 1/2 : 175 days 1.5 mg MWCNT/m³ - terminal t: 1/2 : 428 days 6 mg MWCNT/m³ - terminal t: 1/2 : 788 days Overload-Threshold 1 Depos pulmonary MWCNT mg [ ] m³ Principal hypothesis: the effect follows the cumulative dose and acute-on-chronic effects should be negligible. 5 postexposure period

26 Conclusion The Effect-Threshold is determined by the threshold of increased V d. This threshold appears to apply to all low-toxicity PSPs for both rats and humans. Inhalation studies should be designed to meet the kinetic cornerstones of generic PSPs and observing the kinetic MTD (t 1/2 > 1 year). NOAEL f cum 1l r.29m³ mg l 1 Depos pulmonary mg [ ] m³ The metric of dose must be defined by the mechanism of target organ injury which is the volumetric overload of alveolar macrophages. Therefore, the most important metrics for the OEL-derivation of Poorly Soluble Particle-like structures is the agglomerate/aggregate volume. OEL generic.5 l m³ respirable AF AF lung burden A/ H clearance A/ H 1 agglomerate Adequately designed and executed 4-week inhalation studies can reliably predict the chronic OELs of low-toxicity PSPs in the absence of overriding lungoverload-related confounders. 26

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