Chemical Risks in Agriculture: Respiratory Diseases and Toxic Gases

1. TTS 2005Chemical risks in agriculture Benoit Nemery, MD, PhD Occupational, Environmental & Insurance Medicine & Pneumology K.U.Leuven, Belgium ben.nemery@med.kuleuven.ac.be

2. Respiratory diseases in agriculture • Infectious micro-organisms • Organic dusts (+ microbial products) • Inorganic dusts (silica, ...) • Chemicals

3. Literature Schenker M.B. (Chair) et al. American Thoracic Society: Respiratory Health Hazards in Agriculture. Am J Respir Crit Care Med, 1998, 158, S1-S76.

4. Chemical exposures in agriculture • Toxic gases • Biocides and pesticides • Fertilizers • Feed additives

5. Toxic gases • Combustion • Decomposition gases • Manure • Silo gases

6. +++ NH3, SO2 , HCl, R-CHO, ... ++ Cl2, CH3NCO, ... + O3, NO2, COCl2, ... solvents, anaesthetics C6H6, CHCl3, F3C-CHBrCl, ... lipid soluble Pleura Respiratory uptake of gases → irritation Water solubility rapid slow

7. Carbon monoxide (CO) all types of combustionwhen O2 supply < exhaust of gases • indoor burning of biomass, wood, charcoal, coal, kerosene, diesel, gas, … • fires, stoves, ovens, heaters, vehicles, engines, compressors, … + insufficient ventilation (indoor confined spaces) ! also NOx and particles

8. Decomposition gases • Storage & putrefaction of organic matter • Liquid manure (pigs, cattle) • Solid manure (poultry) • production of H2S, CH4, NH3, CO2, CO • accidental exposure (agitation + pumping of liquid manure, repairs) • chronic exposure in animal confinement buildings

9. Liquid manure storage • Hydrogen sulfide (H2S) • heavier than air • odour +++ (except > 150 ppm); irritant ++ • neurotoxicity (→ coma) • respiratory toxicity (→ lung oedema) • “dung lung” • + CH4, CO2, … → O2 depletion • asphyxia

10. Irritant gases • Ammonia (NH3) • highly water soluble and potent irritant • affects mainly eyes, nose, upper airways • exposure levels often exceed recommended TLV (25 ppm, 8 h), but no evidence that NH3 leads to excess symptoms or chronic airways disease • possible accidental exposure to high amounts when use of anhydrous ammonia (fertilizer)

11. Acute inhalation of NH3 Leduc et al. Thorax, 1992, 47, 755-7 Man, 28 y • explosion of tank in refrigeration plant (NH3) • acute: • corneal & dermal lesions • tracheobronchitis • respiratory insufficency • 12 y later: • severe airway obstruction • bronchiectases

12. Storage of forage/grain in silos • Open silo - Trench or bunker • Sealed silo Fermentation of silage • multiplying bacteria consume oxygen • generation of CO2 and organic acids • generation of nitrogen oxides plant nitrates → NO → NO2, … ! Rapid process (hours)

13. Irritant gases • Nitrogen dioxide (NO2) • Heavier than air • Invisible → yellowish → orange-brown • (Sweet smell) • Poorly water soluble • Poor warning properties (mild irritation) • Potent oxidant • May cause delayed lung injury (permeability lung oedema)

14. Douglas W.M., Hepper N.G.G., Colby T.V. Silo-Filler’s Disease. Mayo Clin Proc 1989, 64, 291-304

15. Silo-filler’s disease Upon entering recently filled silo • asphyxia • airway irritation • after 4-24 h: non-cardiogenic lung oedema - chemical pneumonitis (“silo filler’s disease”) • after 3-4 weeks: bronchiolitis obliterans (+ malaise, fever, … DD. Miliary TB)

16. Case • Man, 34 y, smoker • Worker in small company making printed circuits • Friday: cleaning galvanisation baths with concentrated HNO3(instead of diluted solution) • During work: mild irritation • At home: progressive cough and dyspnoea “I could not lay down” • During night: hospitalization in respiratory distress

17. NO2-induced pneumonitis

18. Case

19. Chemical exposures in agriculture • Toxic gases • Biocides and pesticides • Fertilizers • Feed additives

20. Biocides and pesticides • Disinfectants • Fumigants • Pesticides

21. Disinfectants • Bleach • Quaternary ammonium compounds • Chloramine T • Aldehydes (formaldehyde, glutaraldehyde, glyoxal) • airway irritation • allergic sensitization

22. Bleach • Bleach (HClO) or “Bleach tablets” + water ! Mixing incompatibilities • Bleach + acids → Cl2, HCl • Bleach + ammonia → chloramines NH2Cl, NHCl2, NCl3 • tracheo-bronchial irritation • chemical pneumonia • irritant-induced asthma

23. Repeated exposure to cleaning agents • Higher risk of asthma in female cleaners • Zock et al. SJWEH 2001, 27, 76-81: P.R. 1.7 • Karjalainen et al. ERJ 2002, 19, 90-5: R.R. 1.50 • Medina-Ramon et al. Thorax 2003, 58, 950-4: O.R. 1.46 • exposure to irritants and sprays ? • “hidden sensitizers”? • Quaternary ammonium compounds (disinfectants / preservatives) • Isothiazolinones (preservatives) • Ethanol amines (wax-removal agents) • d-limonene, terpenes (perfumes)

24. Quaternary Ammonium Compounds • In pig farmers with frequent exposure to QAC sprayed under high pressure, higher risk of • asthma-like symptoms • low lung function • atopic sensitization • bronchial hyperreactivity Preller et al. OEM 1995, 52, 654-660 Preller et al. ERJ 1996, 9, 1407-1413 Vogelzang et al. IAOEH 1997, 70, 327-333

25. Fumigation and pest treatment Treatment of soil, barn, greenhouse, … with highly toxic volatile compounds • methyl bromide (CH3Br) • hydrogen cyanide (HCN) & other cyanides • carbon disulfide (CS2) • ethylene oxide • acrolein • chloropicrin • zinc phosphide (Zn3P2) →H3P • asphyxia • respiratory irritation • neurotoxicity

26. Sulfurization Koksal N. et al. Apricot sulfurization: an occupation that induces an asthma-like syndrome in agricultural environments. Am J Ind Med 2003, 43, 447-453 • Malatya (Turkey) • 15 apricot farms, 69 workers (31 y) • 20-25 days in summer • Melting of S → SO2 in sulfurization chambers (8-10 h) • Repeated exposures for ~1 h to 100-700 ppm SO2 • Acute eye, nose and airway irritation (including wheezing in 6) • Acute decreases in FEV1 (-0.39 L, >20% in 10) and FVC (-0.16 L)

27. Pesticides • Substances intended for preventing, destroying, repelling, mitigating pests (“toxic by design”) • Target specificity: • Insecticides • Fungicides • Herbicides • Rodenticides • Acaricides • Nematocides • heterogeneous chemicals

28. Agricultural pesticides Occupational and para-occupational exposures • Mixing and loading • Application (tractor, airplane, backpack) • Field workers (harvesting, handling) • Bystanders (! children) • Residents • Misuse and accidental exposure • Spills (mass-poisoning) • Accidental ingestion • Suicide • Homicide

29. Agricultural pesticides • Most pesticides have low volatility • Inhalation exposure is generally low • Large size droplets ! Indoor spraying (greenhouses) • Most occupational exposure is by dermal route ! Protective clothing • In general: few serious and specific respiratory effects reported, even after spraying

30. Agricultural pesticides Hoppin J.A. et al. Chemical predictors of wheeze among farmer pesticide applicators in the Agricultural Health Study. Am J Respir Crit Care Med 2002, 165, 683-689 • Cohort of >20,000 pesticide applicators in Iowa & North Carolina • Questionnaire: 19% wheeze in past year •  adjusted OR for wheeze for exposure to paraquat, three organophosphates (parathion OR=1.5), one thiocarbamate, atrazine • Significance?

31. Agricultural pesticides • In general: few serious and specific respiratory effects reported, even after spraying ! Acute intoxication (accident or suicide) with organophosphates or paraquat

32. Eddleston M. et al. Pesticide poisoning in the developing world - a minimum pesticides list. Lancet 2002, 360:1163-7. Chandigahr, India Sri Lanka 2 districts Ban of parathion Controlled availability Samoa Amman, Jordania

33. Organophosphates Parathion (E605, …), ... • Excellent penetration through skin & mucosae • inhibition of acetylcholinesterase • Diarrhoea, sweating, salivation, lachrymation, miosis, bronchospasm, bronchorrhoea (pulmonary oedema) • Muscle fibrillation→weakness → paralysis • CNS (anxiety, vertigo, tremor) → convulsions → coma • Delayed neurological effects possible

34. + + N-CH3 CH3-N Paraquat 1,1’-dimethyl-4,4’-bipyridylium chloride • Contact herbicide • Water-soluble concentrates 100-200 g/L • (Gramoxone, Dextrone) • Granular formulations 25-80 g/kg • (Weedol, ...)

35. Paraquat • Local toxicity: skin, nails, eyes, nose • Systemic toxicity after • ingestion (accidental, suicidal) • dermal absorption • poor penetration through intact skin • absorption and (fatal) toxicity possible if • Prolonged skin contact (leaking spray equipment) • Skin damage • Contact with concentrated solution • no substantial uptake via inhalation (droplet size > 200 µm)

36. Paraquat • Systemic toxicity to various organs, especially lungs • Accumulation in lung tissue: active uptake in pneumocytes (via polyamine uptake system) • Oxidative stress

37. NADPH NADP+ NADPH reductase PQ++ PQ+. . . OH _ O2 O2 . NADP+ GSSG GSH Lipid peroxidation Vit.E, C Lipids Enzymes DNA Fe SOD H2O2 H2O CAT

38. Paraquat • Water-soluble concentrate: 100-200 g/L • < 20 mg PQ/kg: • Mild g-i symptoms • 20-40 mg PQ/kg: • Malaise, g-i symptoms • Renal failure • Pulmonary fibrosis→ death in 2-3 wks • > 40 mg PQ/kg (15 ml of 20% solution): • Multiorgan failure → death in <1 week

39. Paraquat Proudfoot et al. Lancet, 1979, 2, 330-332

40. Paraquat • Long-term effects of chronic paraquat exposure? • Schenker M.B. et al. Pulmonary function and exercise-associated changes with chronic low-level paraquat exposure. Am J Respir Crit Care Med, 2004, 170, 773-779 • Costa Rica • 338 plantation workers (banana, coffee, palm oil), 37 y • 66% paraquat handlers; index of cumulative exposure • slight increase in prevalence of chronic cough • no significant effect on spirometry and DLco • slight effect on gas exchange during maximal exercise (200 subjects < 40y) : SpO2>5% (pulse oximetry) associated with higher PQ index • Subtle long-term effect on lung parenchyma?

41. Thank youTeşekkür Ederim ben.nemery@med.kuleuven.ac.be