1. Herbicides
Aaron Ralston, DO

2.
Events

3. Objectives Discuss the clinical toxicity from 2-4 D
Discuss the studies looking at chronic effects of glyphosate
Discuss the management and assessment of paraquat and diquat poisoning

4. 2-4 Dichlorophenoxyacetic Acid

5. Others. 2,4-D 5th most common in USA (2001) but most common for domestic use

6. TCDD Dioxin contaminant
Agent Orange
2,4-D and 2,4,5-T
TCDD Dioxin contaminant
2,3,7,8-tetrachlorodibenzodioxin

7. Mechanism of Toxicity: Incompletely Characterized
Corrosive
Multisystem: Non specific or basic functional effect
Oxidative phosphorylation, voltage-gated chloride channels
or similarity to acetic acid and acetyl co-A
Surfactant effect?

8. Clinical Manifestations
GI, Muscular and CNS
Vomiting, myotonia and miosis.
Peaks hrs and lasts several days.
2,4-D higher mortality than MCPP.
Respiratory alkalosis or metabolic acidosis
Fasciculations
Death is delayed a few days.

9. Management Supportive Maintain good urine output
Urinary alkalinization
Plasma alkalinization HD

10. Glyphosate Inhibits an enzyme only present in plants
GI effects is most common clinical manifestation after oral overdose
Irritant and caustic in high concentration preparations
Specific clinical toxicity may vary by formulation (e.g., Potassium salt or isopropylamine)
Surfactant toxicity
CV collapse in large exposures
Treatment supportive

11. Glyphosate and Cancer
Worldwide use increased by the creation of glyphosate resistant genetically modified plants
IARC declared it is a probable carcinogen in 2015
Based on a case control study
Non Hodgkin’s Lymphoma
Based on animal studies
European Union review did not concur

12. Paraquat and Diquat Bipyridyl compounds Paraquat has a high mortality
10-20 ml of 20% soln is fatal

13. Superoxide leads to generation of other free radicals
1- PQT is oxidized
2-PQT radical is reduced by diaphorase and NADPH
back to PQT Leading to redox cycling and generation of superoxide

14. Redox-Cycling
As long as NADPH and Oxygen are available, PQT cycles and produces free radicals.
This leads to depletion of NADPH which leads to depletion of Glutathione
Glutathione is also depleted by the free radicals.
Eventually cell necrosis occurs and macrophages arrive leading to inflammation and fibrosis.

15. Pharmacokinetics Low oral bioavailability
Peak at 1 hour
Even lower absorption through skin and lungs
Cleared renally unchanged. Terminal elimination half life is prolonged (80 hours)

16. Clinical Toxicity Dermal or eye exposures: irritation or ulceration
Oral exposure:
Pulmonary (not common in diquat because it does not concentrate in the lungs)
Acute pneumonitis
Pulmonary fibrosis
Role of oxygen?
Renal

17. Diagnostic Testing
Urinary dithionite test is a simple and quick method for confirming (or excluding) paraquat and diquat poisoning.
Various methods are reported, including the addition of 1 g of sodium bicarbonate and 1 g of sodium dithionite, to 10 mL of urine.
A color change (blue for paraquat and green for diquat) confirms ingestion—the darker the color the higher the concentration.
If the test is negative on urine beyond 6 hours after ingestion, a large exposure is unlikely, but repeat testing should be conducted over 24 hours.

18. Copyright © 2014 McGraw-Hill Education. All rights reserved.
From: Chapter 115. Herbicides
Goldfrank's Toxicologic Emergencies, 9e, 2011
Legend:
Nomograms for serum paraquat concentrations. A. Compilation of three nomograms proposed by: Proudfoot et al.96a Scherrmann et al.107a and Jones et al.58a B. Hart paraquat nonogram. Hart et al.43a In A, concentrations below lines predict survival. In B, lines link concentrations of equal probability of survival. (Derived from Eddleston, et al.33 by permission of Oxford University Press.)
Date of download: 10/13/2014
Copyright © 2014 McGraw-Hill Education. All rights reserved.

19. Copyright © 2014 McGraw-Hill Education. All rights reserved.
From: Chapter 115. Herbicides
Goldfrank's Toxicologic Emergencies, 9e, 2011
Legend:
Nomograms for serum paraquat concentrations. A. Compilation of three nomograms proposed by: Proudfoot et al.96a Scherrmann et al.107a and Jones et al.58a B. Hart paraquat nonogram. Hart et al.43a In A, concentrations below lines predict survival. In B, lines link concentrations of equal probability of survival. (Derived from Eddleston, et al.33 by permission of Oxford University Press.)
Date of download: 10/13/2014
Copyright © 2014 McGraw-Hill Education. All rights reserved.

20. Serum Creatinine
Elevation can serve as marker of poor prognosis

21. Management Charcoal, NAC, Vit C, Vit E Immunosuppressants
Steroids
Cyclophosphamide
Early charcoal hemoperfusion

22. Thank you