Toxicology and Metabolism Relating to Occupational and Residential

Chemical Exposures

Robert I. Krieger1, Jeffrey H. Driver2,3, John H.Ross2,4

1Personal Chemical Exposure Program, Dept. of Entomology, University of California, Riverside, 2infoscientific.com, Inc.,

Manassas, VA3 and Carmichael, CA3

Chemical Exposure

Chemical contact with potential absorption• Ingest, inhale, touch• Amount [dose (mg), dosage (mg/kg)]• Time [acute, short term, chronic]• Response [benignNOEL,NOAEL to lethalLD50]

Determinants of quality and longer life include lower incidence of disease, fewer accidental deaths, a safer food supply, and access to improved

pharmaceuticals, pesticides and numerous other chemical technologies.

Age-Adjusted Death Rates by Class of Injury, U.S.A. (1910-2004)

Dea

th R

ates

a

Pesticide and Chemical Human Exposure Classes

• Accidental– Workplace (U.S. National Safety Council)– Home (young children, U.S.A.)

• Unintended– Occupational– Residential

• Unavoidable – Food – Water – Air – Surfaces

Research Strategy PCEP, UCR after Collins, IUPAC

• Commodity chemicals exposures–2,4-D, OPs, chlorpyrifos, malathion, captan–Variety of use conditions (not scenarios)

• Generic exposure biomarkers–Acquire environmental data–Aggregate exposure potential

• Proprietary chemicals stewardship–Speeds product registrations–Uses validated exposure data

Well known safe uses of commodity chemicals, to study generic exposure factors, to promote the registration, stewardship and general knowledge of prorietary products.

Accidental Pesticide Exposures

• Rare (catastrophic)• Short term (seconds, min, hrs, days)• Response: toxicity

– Death (LD50)– Target organ effects (ED50)

• Regulation– Restricted Materials & Engineering Controls– Training for safe use– Personal Protective Equipment

Leading Causes of Death U. S. A., 2004

All causes 2,443,000

Heart disease 697,000

Cancer 557,000

Stroke 163,000

Chronic lung disease 125,000

Unintentional injuries 107,000Diabetes 73,000

Flu 66,000

Deaths, 2004 Total Rate/million

All unintentional injuries 111,000 378Motor vehicle accidents 46,200 157Falls 20,200 69Poisoning 13,300 45Choking 4,900 17Fires and smoke 3,900 13Drowning 3,800 13Suffocation 1,300 4Heat or cold 1,200 4

All others 16,200 55

Accidental U. S. Deaths, National Safety Council, 2005-2006

All U. S. Deaths Due to Injury

Death x 1000

Year 2002 2001 2000Transportation 107 102 98Non-transportation 58 54 51Venomous animals and plants 0.076 0.061 0.080Poisoning 18 14 13Pesticide (0.007; 2002)

Suicide 32 31 29Undetermined intent

(poisoning)3 3 3

Medicine and surgery 3 3 3

Unintended Pesticide Exposures

• Common (residues from safe use) – Agricultural “Integrated Pest Management”– Residential “Pest Control”

• Short term (min, hr, d, wks to yrs)• Responses: No Observed Adverse Effects• Regulations minimize continuing, low level

pesticide contacts

Handlers

Pesticide Handler Exposure Database (PHED)

• Generic for active ingredient residue– Application rate (mg/kg applied→mg/person)– Formulation– Passive dosimetry– Defaults

• Time• Clothing penetration• Dermal absorption

• Urine biomarker (ug/kg bw)

SCENARIO 34. LIQUID/OPEN POUR/BACKPACK (MLAP)Dermal Exposure

Clothing Scenario

Head and Neck (mg/lb aihandled)

+ Upper and Lower Arm, Chest, Back, Thigh

and Lower Leg(mg/lb ai handled)

+ Hand (mg/lb aihandled)

TOTALDermal Exposure

(mg/lb ai handled)

No Clothing 0.742 22.1 No Data = All glove data

Single Layer,No Gloves

0.742 1.72 No Data All glove data

Single Layer,Gloves

0.742 1.72 0.00462 2.5

PHED: Backpack Pesticide Exposure Estimate

Deposition is a physical process (particle behavior)

Harvesters

Field (Re)Entry: Absorbed Dosage by Exposure Routea

Field (Field (Re)EntryRe)Entry: Absorbed Dosage by : Absorbed Dosage by Exposure Exposure RouteRouteaa

SKIN INHALATION

92 + 6% 8 + 6%

a based upon 11 tasks, California EPA

CALCULATING HARVESTER FIELD ENTRY EXPOSURE

CALCULATING HARVESTER FIELD ENTRY EXPOSURE

Absorbed Daily

Dosage=

foliarresidue

transfercoefficient

hoursworked

dermalpenetr.

body weight

(ug/cm2) (cm2/hour) (hrs) (%) kg body weight

DFR

• DFR: Dislodgeable Foliar Residue (ug/cm2)– LP: Leaf Punch Samples– WL: Whole Leaf Samples

• TSR: Transferable Surface Residue (ug/cm2)– BSR: Benchtop Surface Roller– ASW: Automated Surface Wipe

Dilute Aqueous Detergent Rinse

vs. Contact Transfer

Leaf Punch

Automated Surface Wipe (ASW) Benchtop Surface Roller (BSR)

DFR and TSR on Strawberry Leaves in Santa Maria

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

DAY 1 DAY 2

ug/c

m2

DFR-WL

DFR-LP

BSRASW

Hand Protection•Exposure reduction

•Food Safety

Biomonitoring

21-30 ug/cm2

11-20 ug/cm2

6-10 ug/cm2

1-5 ug/cm2

RESIDENCE FOGGERSRIVERSIDE APARTMENT

Estimated Chlorpyrifos Exposure from Indoor Broadcast Use

Study Estimated Dosage (ug/kg)

Berteau et al. (1989) 2700Nafzigger (1985) 38Fenske et al. (1990) 75-160Vacaro et al. (1990) 21-31Ross et al. (1990) 7-25Gurunathan (1998) 64-356Krieger et al. (2001) 1-3

How Can There Be 1,000-Fold Difference for One Chemical?

• Regulatory concern mandates overestimates• Hypothesized importance of a particular exposure route• Use of non-validated models vs. measurements from

individuals• Use of methods never quantitatively related to human

exposure• Structured activity vs. Situational biomonitoring

Biomonitoring Is a Gold Standardfor Model Validation

Biomonitoring MODEL Env Monitoring⎯ →⎯⎯⎯⎯⎯⎯ ← ⎯⎯⎯⎯⎯⎯⎯⎯

.

ValidationHuman Biomarkers → Exposure ← Environmental Residues

Registration EligibilityDecision (RED) Exposure Values

• EPA for 1996 FQPA and 1988 FIFRA• Estimates

– Dietary– Drinking water – Residential

• Indoor• Outdoor

– Occupational

OP REDs vs. DAP Biomonitoring 0.30 ug/kg

Dietary, chronic

1.167

Water 5.99

Residential 23.7

REDs Total = 30.9 ug/kg

The Case for Biomonitoring and Aggregate Exposure Estimates

• Cumulative estimates require adding aggregates from individual pesticides

• Errors from each aggregate exposure multiply with cumulative estimate

• Best exposure estimates are measured closest to person, not closest to source

Biomonitoring Uncertainties

• Biomarker >> parent in/on food, in water, on foliage or residential surfaces

• Biomarker may be well absorbed dermally• Biomarker is well absorbed orally (from food or hand-to-

mouth)• Biomarker is frequently more environmentally stable

than parent pesticide e.g., CP and TCP or CP and Diethyl phosphate

Dietary DAPs Confound Estimates of OP Exposure Based on Biomonitoring

• 33 Produce types monitored at the farm gate• All samples selected contained measurable OPs• 66% had more DAP biomarker than parent OP• Mole ratio of DAP/OP = 0.1-73• DAPs are less-well absorbed orally, but if DAP>OP, a

large, significant overestimate of OP exposure will occur Zhang and Krieger, 2004

Studying Residential Exposure Structured vs. Situational

STRUCTURED (Experimental)- Simulated Activities: Crawling, Playing- Jazzercise: Timed Activity Choreographed to

Music

OPPORTUNISTIC- Situational Exposure: Monitoring Residents

Living in Treated Area After Known Application- Population Surveys: Random Sampling of

Representative Population (U. S. CDC)

Structured ActivityPassive Whole Body Dosimetry & Biomonitoring

High contact, 20 min exposure

Choreographed Turf & Carpet Studies (excluding Black 1993) vsSituational Turf & Carpet Studies (excluding CDC 2,4-D 2003 and Black 1993):

Dermal Exposure Rate (DE) vs Tranferable Residues (TR)

y = 0.6916x + 4.6987R2 = 0.7167

0.0000

1.0000

2.0000

3.0000

4.0000

5.0000

-4.0000 -3.0000 -2.0000 -1.0000 0.0000 1.0000TR (log ug/cm2)

DE

(log

ug/h

r)

y = 0.6776x + 3.4242R2 = 0.9699

Without doubt…

FoodAir

Water

Unavoidable chemical exposures

Chemical residues, signatures of thriving in the 21st Century

“More and more about less and less”

Demonstrate the power of advanced analytical chemistry and the naiveté of myopic policy-makers and the public.

The persistence issue is an opportunity for teaching and enlightenment!

POPs

CDC Biomonitoring 21st Century Chemical Biomarkers

Ever-present signs of life in blood and urine of the living

“the most comprehensive assessment of chemical contamination in individuals ever performed.”

Environmental Biomonitoring Chemical Inventories

• CDC/March 2001 27 chemicals

• CDC/January 2003 116

• CDC/June 2005 143

• EWG/Mt.Sinai 167 (total, n = 9)

Stimulates media fear-mongering and reports that alarm the chemically naïve public who are then bombarded with scary lists of health hazards; and, finally the sponsors seek more regulation of vanishingly small, benign amounts of chemicals in blood and/or urine.

CDC 3rd Report of 2005, 143 chemicals; promises 300 by 2007 and perhaps 700 by 2011!

Valuable perspective on pesticides, but present metabolite misclassification needs revision. Active ingredients are not that persistent.

U. S. Communicable Disease Center 3rd Report on Chemical Exposure, 2005

• Organochlorine Pesticides

• Organophosphate Pesticide

• Pyrethroids Pesticides (sic)• Carbamate Insecticides• Herbicides• Other Pesticides

• Organochlorine Pesticides and Biomarkers

• Organophosphorous Pesticides and General Biomarkers

• Organophosphorous Pesticides and Specific Biomarkers

• Pyrethroid Pesticide Biomarkers• N-Methyl Carbamate Biomarkers• Herbicidal Pesticides and Biomarkers• Other Pesticides and Biomarkers

Present Misclassification Suggested

Pesticide Use andHuman Chemical Exposureare inseparable at some level...whether Accidental, Unintentional or Unavoidable.

Biomarkers in our chemical world can clarify the significance of trace amounts…

There is a safe level of everything!

Personal Chemical Exposure ProgramDepartment of Entomology

University of California, Riverside, CA 92521Bob Krieger, Ph.D. (951) 827-3724

email: bob.krieger@ucr.eduhttp://faculty.ucr.edu/~krieger/

Pesticide Groups(Collins, IUPAC 2006)

• Commodity (1950s to present)

• Generic (1960-70s to present)

• Proprietary (1970s to present)

• Rich environmental data and first human exposure studies

• Early human exposure studies of handlers and harvester

• Environmental residues and human biomarker studies