Assessing Current Health Threats from Past Exposure to ...

Assessing Current Health Threats from Past Exposure to Novel Agents: Lessons Learned from Military OccupationsMelissa A. McDiarmid, MD, MPH; Stella E. Hines, MD, MSPH; Katherine Squibb, PhD; and Joanna M. Gaitens, PhD"

Western Occupational Health Conference: September 25 – 28, 2013 / Sheraton Waikiki, Honolulu, Hawaii"

Assessing Current Health Threats from Past Exposure to Novel Agents: Lessons

Learned from Military Occupations

Content Attestation

We, Melissa A. McDiarmid, MD, Katherine Squibb, PhD, Joanna Gaitens, PhD, and Stella E Hines, MD

hereby declare that the content for this activity, including any

presentation of therapeutic options, is well balanced, unbiased, and to the extent possible,

evidence-based.

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Conflict of Interest Disclosure

We have no financial relationships with commercial entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients relevant to the content we are planning, developing, presenting, or evaluating.



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Assessing Environmental Agent Exposure and Toxicity: The Case of

Depleted Uranium (DU)

Bottom Line Up Front •  Military-unique occupational and

environmental exposures may be determinants of current health status manifesting as both local and systemic effects

•  Careful history taking informs the differential diagnosis and work up

•  Measuring systemic exposure requires careful consideration of matrix selected, timing of sample collection and use of comparison values



Military Uses of DU

•  Tank armor for increased resistance to enemy projectiles

•  Munitions to increase penetrating power

•  Friendly-fire incidents exposed US soldiers to: – DU shrapnel – Aerosolized DU oxides

•  Inhalation, ingestion, wound contamination

Depleted Uranium (DU)

•  By-product of uranium enrichment process through which 235U is extracted from natural uranium for use as nuclear fuel

•  Leftover is “depleted” with 235U/238U

isotopic ratio = 0.245% compared to 0.7% for natural uranium



Assessing Systemic Exposure

•  Whole Body Radiation Counting was not sufficiently sensitive to assess exposure in most of the cohort

•  Urine uranium testing was used to measure systemic body burden

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McDiarmid, et al, Hlth Phys 104:347-361 (2013)

Mean Urine Uranium Values (1993-2011, N=80)

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Correlation of radiographic appearance with histologic appearance. (A) Thick fibrotic capsule with shards of corroded DU in lumen; (B) thick cellular capsule lined by squamous metaplasia, particles, and shards of corroded DU in wall and lumen; (C) particles and shards of disintegrated DU fragment scattered throughout a soft tissue sarcoma.



1995 film 2001 film

Surveillance for Local Tissue Effects

•  Comparison of various imaging modalities to look for indication of fragment change/transformation – Plain film x-ray – Ultrasound – PET-CT scan

•  No PET-CT scans were suggestive of malignancy related to fragments

Summary

•  Past Exposures to Novel Agents during military service may be determinants of current health effects.

•  Depending on the toxicant and storage depot, exposure measurements may be helpful, even for remote past exposure.

•  Retained metal fragments result in local tissue reactions, but also function as a depot permitting on-going toxicant exposure.

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New Approaches in Biomonitoring for Metals and the

Assessment of Health Effects

Use of Isotopic Signatures and Metal Speciation Analysis

Katherine Squibb, PhD

Three Talking Points

•  Biomonitoring programs for certain metals should include speciation analysis to obtain information on specific sources of exposure.

•  Information useful for the assessment of health risks and clinical management of metal exposures can be gained by speciation analysis.

•  Potential health risks of exposure to metals that target the kidney can be examined using urine biomarkers of renal effects.

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Next Step: Measuring DU Concentrations

•  High total U concentrations suggest but do not demonstrate that a Veteran has been exposed to DU.

•  This can be tested directly by measuring the isotopic ratio of the uranium (U) in a urine sample.

•  Why does the U isotopic ratio differ in DU versus natural U?

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U234, U235, U238

Natural U (U235/U238 ratio = 0.0072)

U234, U235, U238

Depleted U (U235/U238 ratio = 0.0023)

U234

U235

U enrichment process



Results of OIF Urine Surveillance (as of 31 December 2011)

*All with DU signature were invited to enter the DU Follow-up Program. Two from OIF/OEF declined but may be interested in future follow-up.

Samples processed 3618

Gulf War I (n=1456) OIF/OEF (n=2162)

Isotopic signature for natural uranium

979

Isotopic signature for natural uranium

2159

Isotopic signature for DU

1*

Isotopic signature for DU

3*

Isotopic analysis not done

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Arsenic Metabolism in Mammals Involves Methylation Followed By Excretion

•  Inorganic As+3 (AsIIIO33-) and As+5 (AsVO4

3-) are converted in mammals to organo compounds by addition of up to three methyl groups: Monomethyl As CH3 AsVO3

2- Dimethyl As (CH3)2AsVO2

1- Trimethyl As (CH3)3AsVO

•  Both the inorganic and the methylated forms are readily excreted in urine following exposure to the inorganic forms

•  In fish and other seafood, As is present as two other organo forms of As (arsenobetaine and arsenocholine) which have low toxicity in humans.

Speciation Analysis of Urine Arsenic



Tubular Lumen

Blood

Blood flow

Glucose

Glucose

Amino acids

Amino acids

LMW proteins: ß2-microglobulin Retinol binding protein α1-microglobulin Blood

LMW proteins

Proximal Tubule Cells

Glomerulus

HMW Proteins: albumin, transferrin, gamma globulins

Cellular enzymes from damaged cells

Organic Ion Uptake and Secretion

PAH PAH

Functional Versus Cytotoxic Effects in Renal Proximal Tubules

Tests of impaired function (protein reabsorption) Low-molecular weight proteinuria Beta-2-microglobulinuria Retinol binding proteinuria Markers of cell injury Enzymuria Alkaline phosphatase,

Gamma-glutamyltransferase Lactate dehydrogenase (LDH) N-acetylglucosaminidase (NAG)

Kidney Injury Molecue-1 (KIM-1)

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Biomarkers of Proximal Tubular Injury

Mann-‐Whitney

Laboratory Test (normal range) Mean ± sem Mean ± sem pKidney Injury Markers

IL-‐18 (0-‐395 ng g creatinine-‐1) 8.75 ± 2.24 6.61 ± 2.68 0.59

KIM-‐1 (kidney injury molecule-‐1)(60-‐837 ng g

creatinine-‐1) 481.37 ± 65.35 885.59 ± 157.01 0.01

NGAL (neutrophil gelatinase-‐associated

lipocalin) (2100-‐9600 ng g creatinine-‐1)649.92 ± 199.07 621.47 ± 84.41 0.13

IAP (Intestinal alkaline phosphatase)

(0.08-‐3.02 U g creatinine-‐1)0.38 ± 0.14 0.99 ± 0.32 0.02

NAG (N-‐acetyl-‐β-‐glucosaminidase)

(0.1-‐5.6 ng g creatinine-‐1)1.41 ± 0.25 1.53 ± 0.54 0.57

Total Protein (0.01-‐0.12 g g creatinine-‐1) 0.17 ± 0.02 0.26 ± 0.07 0.27Low Molecular Weight Proteins

Microalbumin (<24 mg g creatinine-‐1) 16.18 ± 7.25 83.50 ± 66.60 0.19β2Microglobulin (0.02-‐0.76 mg g creatinine-‐1) 1.09 ± 0.41 0.59 ± 0.10 0.59

α1Microglobulin (<5.6 mg g creatinine-‐1) 5.72 ± 1.18 5.88 ± 1.04 0.42Retinol binding protein

(<250 µg g creatinine-‐1)45.18 ± 6.23 71.89 ± 19.27 0.21

O or 1 metal above Reference Values

(n=23)

2 or more metals above Reference Values (n=14)

Biomarkers of Renal Effects When Multiple Metal Exposures Exceed Reference Values



LONG-‐TERM EXPOSURE RELATED TO MILITARY SERVICE: THE CASE OF EMBEDDED (FOREIGN BODY)

FRAGMENTS JOANNA GAITENS, PhD, MSN/MPH, RN

BALTIMORE VA MEDICAL CENTER

This work is supported by the Department of Veterans Affairs and approved by the Baltimore VA Medical Center’s Office of Research and Development and University of Maryland School of

Medicine IRB.

September 2013

BACKGROUND

•  Traumatic injuries via contact with improvised explosive devices (IEDs) the “signature injury” of those who served in Iraq and/or Afghanistan.

–  Over 40,000 soldiers with traumatic injuries may have retained embedded fragments.

–  IEDs are packed with heterogeneous material that may lead to local and systemic adverse health effects.

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IED INJURIES RESULT IN…

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•  Local Effects –  Risk of the development of tumors at the fragment

sites •  Mechanism of tumor development:

–  Foreign body carcinogenesis? Dependent on size and surface characteristics

–  Chemical carcinogenesis? Tissue local to oxidized fragments exposed to carcinogenic metals (e.g. Ni, Cr)

–  Both?

•  Systemic Effects –  Risk of target organ effects arising from chemical

released from the fragments •  Known renal, neurological effects and reproductive of metals

(e.g. Pb, Cd, Ni, Mn, Cu)



MISSION OF TEFSC

•  Established at the Baltimore VA Medical Center

•  To provide care and active medical surveillance for Veterans nationwide with retained embedded fragments

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21,007 (3.6%) Screened Positive

569,608 (96.4%) Screened Negative

10,753 (51.1%) Completed 2nd Screen

2,793 (26.0%) possibly have fragment

2,158 (20.0%) Likely do not have a fragment

4,933 (45.9%) have or had a fragment

1st Screen: Do you have or suspect you have a retained fragment as the result of an injury received while serving in the area of conflict?

590,615 OEF/OIF/OND Veterans Completed 1st Screen

*Completion of the 2nd screen triggers inclusion in the Embedded Fragment Registry

SCREENING RESULTS (AS OF DECEMBER 31, 2012)

2nd Screen*: Were you injured by: - bullet? - blast or explosion?

-in or on vehicle? - source (IED, RPG...)? Fragments removed during surgery? - sent for analysis? Fragments in body? - documented on x-ray?

870 (8.1%) High likelihood of having a fragment

SURVEILLANCE PROTOCOL

•  Characterization of removed fragments

•  Urine biomonitoring via mail

•  Radiologic surveillance of embedded fragment location and shape

•  Target organ surveillance for toxicants of concern

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Learned from DU experience



BIOLOGICAL SPECIMENS ALSO PROVIDE INSIGHT INTO EXPOSURE

24-hour urine specimens •  Toxicants of interest

•  Metals: Al, As, Cd, Cr, Co, Cu, Fe, Mn, Mo, Ni, Pb, U, W, Zn

•  Plastics/polymer components: Isocyanate, Acrylics, Diethylhexylphthalates

•  Others: Based on fragment analysis data

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Why collect urine samples? Why collect urine samples?

INTERPRETATION OF URINE BIOMONITORING RESULTS

•  Results are compared to reference values –  Prefer to use NHANES data

•  95th percentile for adults over age of 20 yrs

•  Available for 7 of the 14 metals

–  In absence of NHANES data we rely on:

•  Clinical Laboratories’ reference range •  Published reference values •  Distribution of our data

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Metal NHANES Data Available

Al As Cd Cr Co Cu Fe Pb Mn Mo Ni W U Zn

IF RESULTS ARE ABOVE THE REFERENCE VALUE…

•  Consider other sources of exposure –  Occupation –  Hobbies –  Metal implants –  Supplements –  Piercings –  Tattoos

•  Consider additional testing –  Blood lead levels if urine lead is elevated –  Speciation testing

•  As speciation to determine inorganic versus organic •  Determination of oxidative states – hexavalent Cr versus total

Cr

•  Repeat urine biomonitoring

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SUMMARY

•  Embedded fragments pose potential local and systemic health effects.

•  Elevated biomonitoring results may signal the release to circulation of metal ions from embedded fragments, allowing their toxicity to threaten organ systems remote from the site of the initial fragment injury.

•  Urine biomonitoring is one element of a comprehensive medical surveillance approach that informs medical management of Veterans with retained metal fragments resulting from traumatic injury.

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Burn Pits and Other Airborne Hazards: Post-Deployment Lung Complaints in Returning Service

Members

Stella E Hines, MD, MSPH The University of Maryland School of Medicine and

Baltimore VA Medical Center Western Occupational Health Conference

2013

Respiratory health complaints in returning Veterans not new: Gulf War I Inhalational Exposures

•  Smoke from burning Oil Well fires (SMOIL)

•  Sand Storms

•  Depleted Uranium –  No differences in

high versus low Uranium exposed populations in:

•  Respiratory symptoms

•  PFTs •  Chest CT

findings h<p://www.evidence.org.kw/photos.php?page=0002_Oil-‐Well-‐Fire-‐and-‐Black-‐Smoke

Hines et al, JOEM 2013



Thus, respiratory complaints in Gulf War I Veterans remain causally unanswered…

•  Single large episode of inhalation of DU particulate does not appear to lead to chronic respiratory disease

•  Patients may still perceive these exposures to be related to their symptoms

OIF/OEF/OND: Recent Conflicts

•  Some old, some new sources of inhalational exposures –  Burn Pits –  Sand Storms –  Sulfur fire @ Mishraq sulfur mine

near Mosul –  Industrial pollution –  Blast Injury –  Tobacco smoke

http://www.wired.com/images_blogs/dangerroom/images/2008/04/24/iraqiexplosion_ied.jpg

Burn Pits

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Photo credit: R. Teichman, WRIISC conference, Aug 2011



Reported Respiratory Health Effects

•  Respiratory Symptoms – (Smith Am J Epi 2009, Smith JOEM 2012)

•  “Asthma” (vs. RADS) - (Szema AJRCCM 2008, Szema JOEM 2011)

•  Constrictive Bronchiolitis – (King NEJM 2011)

•  Acute Eosinophilic Pneumonia – (Shorr JAMA 2004)

•  Interstitial Lung Disease – (Zembrzuska AJRCCM 2011)

•  Allergic Rhinitis – (Szema AJRCCM 2008)

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Institute of Medicine Report, released 2011

•  VA directed IOM to prepare an evaluation of Burn Pit issues and recommendation back to the VA

•  Conclusions – Mixture of chemicals from regional bkgrd & local

sources that contribute to the high PM – Unable to determine whether long-term health

effects likely due to burn pit emissions; •  BUT service in Iraq or Afghanistan might be associated

with long-term health effects (mainly b/c of PM from natural & anthropogenic sources)

– Needs more study

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Summary

•  Veterans possibly experienced inhalational exposures to potential airborne hazards –  High PM concerning

•  Causal associations between burn pit emissions and lung disease not definite

•  A variety of respiratory health effects have been reported

•  Prior military inhalational exposures may influence current respiratory health

•  Clinician must ask about this

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