1. Pesticide Illness Part 3 Fumigants, Fungicides, Herbicides, Disinfectants, Miscellaneous Pesticides Prepared by: Rupali Das, MD, MPH, California Department of Health Services, Michael O’Malley, MD, MPH, University of California, Davis, Laura Styles, MPH, Public Health Institute

2. 2 Toxicology, Diagnosis & Management of Pesticide Illness by Functional Category IIIInsecticides FFFFumigants FFFFungicides HHHHerbicides DDDDisinfectants MMMMiscellaneous

3. 3 Fumigants  Halogenated hydrocarbons –Methyl bromide –Ethylene dibromide, DBCP  Inorganic compounds –Sulfuryl fluoride  Pro-fumigants –Metam sodium  Metal phosphides –Aluminum, Zinc, Magnesium US DOT

4. 4 Fumigants Methyl Bromide  High vapor pressure  Heavier than air  Odorless –Chloropicrin added  Toxic mechanism –Tissue methylation

5. 5 Methyl Bromide Acute Toxicity  Vesicant –Blistering dermatitis  Lower respiratory toxicant –Delayed pulmonary edema  Central nervous system depressant –Usual cause of death

6. 6 Methyl Bromide Acute Toxicity Differential Diagnosis  CNS depression –Other CNS depressants  Pulmonary edema –Hepatic & renal disease –Acute severe asthma

7. 7 Methyl Bromide Acute Toxicity Management  Serum bromide levels –3-6 ppm: Possible exposure –>15 ppm: Acute poisoning –>50 ppm: Severe poisoning/ death  Treatment –Symptomatic Bromide levels - Reporting units  ppm = mg/liter  mg/L=10 mg /deciliter (USA)  ppm = 80 milli-equivalents (meq)/liter (European)

8. 8 Methyl Bromide Chronic Toxicity  Central nervous system –Cognitive, behavioral effects –Polyneuropathy  Reproductive system –Teratogen –Genotoxic, mutagenic

9. 9 Methyl Bromide Chronic Toxicity Serum Bromide Levels  Long serum half life –11—15 days  Chronic exposure –Asymptomatic high levels possible

10. 10 Case Illness After House Fumigation

11. 11 Illness After House Fumigation Pesticide Application History Uncovered electrical conduit: one pipe had a 2” diameter and the others a 1” diameter Methyl bromide fumigation

12. 12 Illness After House Fumigation Health Effects  Tenant found convulsing on floor the following evening  Serum bromide level 270 ppm  Refractory seizures, intermittent fever, multi-organ failure

13. 13 Methyl Bromide Phase-out  Ozone depletion –“100% reduction” in 2005  Exemptions –Critical agricultural uses –Pre-shipment & quarantine –Emergency uses  No “ideal” substitute Source: US EPA “Frequently Asked Questions” on methyl bromide phase-out

14. 14 Fumigants Sulfuryl Fluoride  Pulmonary –Dyspnea, cough, delayed pulmonary edema, fatal hypoxia  Renal  CNS –Weakness, nausea, vomiting, restlessness, muscle twitching, seizures

15. 15 Fumigants Metam Sodium  Hydrolyzes to mixture of irritants  Health effects –Irritant dermatitis –Reactive airways dysfunction syndrome/asthma

16. 16 Case Transportation Worker with Cough  40 year-old male transportation worker with metallic taste; burning eyes, chest, nose; nausea; dizziness.  Recurrent cough with wheezing, phlegm for 5 days. Chest tightness, dyspnea on exertion.

17. 17 Transportation Worker with Cough Exposure History  Tank car derailment –>19,000 gallons metam sodium released  Worker involved in response to accident –Symptoms onset within 20 minutes –Worked 6.5 hours alongside river

18. 18 Transportation Worker with Cough Physical Evaluation  Exam 6 months later –Mild nasal inflammation, –Spirometry  FEV 1 : 87%, FVC: 101%, FEV 1 /FVC: 69%, FEF 25-75 : 26% –Methacholine challenge test  PC 100 : 1.2 mg/ml (normal >4 mg/ml)

19. 19 Fumigants Chronic Effects NeurologicReproductiveOther Methyl bromide Cognitive, behavioral Animal studies Sulfuryl fluoride Olfactory, cognitive Metam sodium Animal studies RADS, asthma

20. 20 Case Drift After Metam Application  Metam sodium applied to carrot fields  Illness reported among –School children –Workers California Department of Health Services, 2001

21. 21 Drift After Metam Application Investigation Findings  MITC detected at school, beyond 500 foot buffer zone  Workers required to monitor field for odor

22. 22 Fumigants Phosphide Compounds  Metal phosphides hydrolyze –Aluminum, zinc, magnesium  Phosphine –Colorless, fish/garlic odor –Highly explosive, corrosive –Rapidly oxidizes to phosphoric acid

23. 23 Phosphine: Illness Syndromes  May resemble viral syndromes  Pulmonary toxicity  CNS toxicity  Multi-organ failure

24. 24 Case Fatality After In-Transit Fumigation  Unemployed male in railcar fumigated with aluminum phosphide  Badly decomposed body found on arrival at destination Source: BC Workers Comp

25. 25Fungicides  Thiocarbamates –Zineb, maneb, ziram, thiram  Pthalimide derivatives –Captan, captafol,  Substituted aromatics –Chlorothalonil, hexachlorobenzene  Inorganic –Sulfur

26. 26 Health Effects of Fungicides  Acute –Irritant & allergic dermatitis  Chronic –Chronic dermatitis –Possible carcinogens

27. 27 Fungicides: Thiocarbamates  Resemble rubber accelerator thiuram  Sensitization reported in exposed workers S CH 3 NCS CH 3 SCN CH 3 CH 3 S Thiram CH 3 CH 3 NCSZnSCN CH 3 CH 3 SS X>1 X S NHCS CH 2 CH 2 CSMnNH S Ziram Maneb

28. 28 Thiocarbamates Antabuse-like Reactions

29. 29 Case Pear Pickers with Skin Rash  26 people picking pears complained of skin rashes  Physical exam: –Contact dermatitis  Applied five days before: –NAA 800 –Ziram Granuflo USDA Graphics

30. 30 Pear Pickers with Skin Rash Pesticide Application  Workers followed requirements for re-entry  Ziram applications –D'Anjou pears, Golden Delicious apples –Symptoms in Bosc pear pickers only  Postulated mechanism of dermatitis –Sharp latent bud on Bosc pears –Increased susceptibility to dermal irritation

31. 31 Pear Pickers with Skin Rash Regulatory Action  Re-entry interval of 14 days established for formulations of ziram on Bosc pears

32. 32 Fungicides: Captan  Dermatitis  5% of volunteers sensitized

33. 33 Case Nursery Worker with Urticaria  Itching and hives in redwood nursery worker  Chlorothalonil patch test: –Local Type I hypersensitivity  1% chlorothalonil open test –Systemic Type I reaction

34. 34 Chlorothalonil: Pigmentary Changes  Blue-gray pigmentation in antecubital area  Positive skin reaction to chlorothalonil  Diagnosis: Ashy dermatitis

35. 35 Ashy Dermatitis: Mechanism  Disruption of basal membrane of epidermis  Melanin deposits in dermis Panagos et al. 1996

36. 36 Fungicides: Elemental Sulfur  Potent skin irritant –Animal experiments equivocal  Airway irritant

37. 37 Case Applicator With Skin Irritation  Pesticide applicator applied sulfur dust to roses  Contact dermatitis –Burning pain –Maculopapular rash.

38. 38 Sulfur: Allergic Skin Reactions  Positive patch test reactions to sulfur in nursery workers applying sulfur  Case reports support sulfur- induced allergy

39. 39 Postulated Mechanism of Sulfur Irritation and Allergy  Allergic reactions –Oxidation/reduction products  Type IV delayed hypersensitivity

40. 40 Herbicides  Dipyridyl compounds –Paraquat –Diquat  Glyphosate  Phenoxy compounds –2,4,5-trichlorophenoxyacetic acid (2,4,5-T) –2,4 dichlorophenoxyacetic acid (2,4-D)

41. 41 Herbicides: Dipyridyl Compounds  Paraquat  Diquat Source: Finnish Platform of the EU-NGDO Liaison Committee

42. 42 Dipyridyl Compounds: Paraquat  Extremely toxic via ingestion –LD 50 3-5 mg/kg  Toxicity –Skin, pulmonary –Parkinson Disease?

43. 43 Paraquat Toxicity Botella et al, 1985 Hoffer and Teitelman, 1989

44. 44 Paraquat (PQ) PQ Alveolar cell membrane PQ 2+ O2O2 O2-O2- Lipid peroxidation Cell death Paraquat Toxicity: Ingestion 1111-4 days –G–G–G–GI tract edema, ulcers 22224-72 hours –H–H–H–Hepatocellular injury –A–A–A–Acute tubular necrosis 77772-96 hours –P–P–P–Pulmonary fibrosis NADPHNADP +

45. 45 Outcome Urine level, 24 hours (mg/mL) 1 Plasma level (mg/kg) 2 Survival likely <1 < 20 Pulmonary fibrosis 1-100020-40 Death within 24 hours 10-10,000 > 40mg Paraquat Levels Predict Outcome

46. 46 Paraquat Toxicity: Treatment  Skin, Eye Decontamination  GI decontamination  Fluids  Hemoperfusion  Oxygen contraindicated  Severe cases –High dose steroids and cyclophosphamide

47. 47 Case Farmer Attempts Suicide  46 year-old male farmer intentionally ingested a greenish liquid.  Complains of dysphagia, sore throat. Previous history of depression.  Profuse, prolonged vomiting  Plasma paraquat at 4 hours –3 mg/mL

48. 48 Farmer Attempts Suicide Hospital Course  Day 2: Severe dysphagia  Day 3: SOB  Day 4-9: pO 2 33.  Day 12: Pt died due to respiratory failure.

49. 49 Herbicides: Glyphosate  Health effects –Case reports of eye, skin irritation –Death due to ingestion of large amounts –Experimental studies fail to show skin irritation  Mechanism of human toxicity unknown –Surfactant preservative?

50. 50 Chlorophenoxy Herbicides  2,4,5-trichlorophenoxyacetic acid (2,4,5-T) –Derived from tetrachlorobenzene –Dioxin byproducts  2,4-dichlorophenoxyacetic acid (2,4-D) –Derived from phenol –Dioxin contaminants not present

51. 51 Chlorophenoxy Herbicides  Acute –CNS depression –Skin, GI, mucous membrane irritation –Renal failure, myopathy  Chronic –Anemia, hepatic, renal effects –Tumor formation(?)

52. 52 Antimicrobials & Disinfectants  Sodium hypochlorite  Isopropyl alcohol  Gluteraldehyde, formaldehyde  Mixtures –NaOCl + H + => Cl 2 –NaOCl + NH 3 => NHCl 2, NH 2 Cl

53. 53 Chlorine Disinfectant Mixtures Toxicity  Acute –Asthma exacerbation, bronchitis  Chronic: –RADS  Treatment –Oxygen, bronchodilators

54. 54 Case Custodian with Shortness of Breath  29 year-old custodian with cough, sore throat, shortness of breath after mixing bleach and ammonia  Exam: –Cough, dyspnea, RR=36; –Lungs: rales & wheezes; –O 2 saturation 94% on room air –PEFR 80%

55. 55 Miscellaneous Pesticides  Propargite (Omite)  Diethyltoluamide (DEET)

56. 56 Acaricide Propargite Contact Dermatitis  Sustained-release propargite  Severe dermatitis with scarring

57. 57  Skin –Irritation –Contact urticaria  CNS –Seizures, encephalopathy  Children < 5 years  High dose/concentrations Insect Repellant DEET Acute Toxicity

58. 58 Acute Toxicity Summary  Organs most often affected –Skin –Lungs –CNS  Severity greatest in developing nations  Exposures occur at work, home, etc.  Prevention: regulation, substitution