and 2-methyl-4-chlorophenoxyacetic acid (MCPA) poisoning could be a bad combination

Authors: Betty SH Chan, Angela L Chiew, Sarah Grainger, Colin B Page, CAlan Gault, Ahmed Mostafa, Michael S Roberts, Nicholas A Buckley, Geoffrey K Isbister

Sir,

We would like to provide further research findings following the case reports on “2-methyl-4- chlorophenoxyacetic acid (MCPA) and bromoxynil ingestion” by Chiew et al. [1]. This reported a characteristic toxicity profile of hyperthermia, hypercapnia and metabolic acidosis in two patients that responded to aggressive active cooling and supportive treatment.

Both MCPA and bromoxynil can cause cellular dysfunction from uncoupling of oxidative phosphorylation and disrupting lipid peroxidation [2]. However, MCPA appears to mainly cause gastrointestinal effects resulting in hypovolemia, rhabdomyolysis, hepatitis and renal failure. It may sometimes cause vasodilatory shock and myocardial toxicity and has a 5–20% mortality rate [2–4]. Less is known about the acute toxicity of bromoxynil, a benzonitrile herbicide. Small studies suggest that related ioxynil compounds have a high mortality rate (64%) and a similar characteristic toxidrome with tachycardia, hyperthermia, increased carbon dioxide (CO2) production, sweating, coma and asystolic cardiac arrest [4,5]. We undertook a retrospective study of all acute bromoxynil and/or MCPA poisonings referred through the New South Wales Poisons Information Centre and three clinical toxicology units (Prince of Wales Hospital, Mater Calvary Hospital and Princess Alexandra Hospital). The data was cross referenced with the National Coronial Information System (NCIS) in Australia. Bromoxynil and MCPA serum concentrations were measured using liquid chromatography mass spectrophotometry in six fatal cases.

From January 2010 to August 2016, there were 22 cases. 20 had ingested MCPA with other such as or bromoxynil. (Table 1). There were two fatal cases that reported just bromoxynil ingestion but both had detectable MCPA concentrations (Tables 1 and 2). Hence all 22 cases had ingested MCPA. Of these, eight had also taken dicamba or other herbicides and 14 had co-ingested bromoxynil (Table 1). This includes the two cases that Chiew et al. [1] reported. There were eight fatalities, seven were characterized by tachycardia, tachypnoea, hyperthermia, rising CO2 production, acidosis and sudden asystolic arrest. Death occurred between 12 and 30 hours post-ingestion. The median maximum temperature and partial pressure of CO2 were 39.3 C (range: 37.9–43 C) and 80mmHg (range: 44–122 mmHg), respectively. Of the seven fatalities with this

Table 1. Deliberate bromoxynil and or MCPA poisoning.

Age Sex Toxin/route Others Outcome 27 F MCPA (i.v.) Dicamba A 49 M MCPA(p.o.) Menthol A Dicamba 35 M MCPA(p.o.) Dicamba A 44 M MCPA(p.o.) Dicamba A 50 M MCPA(p.o.) Dicamba A 52 F MCPA(p.o.) Dicamba A 46 M MCPA(p.o.) Moxidectin D 70 F MCPA(p.o.) Dicamba D 53 F Bromoxynil (p.o.)a , D bromadiolone 46 M MCPA, bromoxynil (p.o.) A 78 M MCPA, bromoxynil (p.o.) D Unknown F MCPA, bromoxynil (p.o.) A 40 F MCPA, bromoxynil (p.o.) A 30 F MCPA, bromoxynil (p.o.) A 26 M MCPA, bromoxynil (p.o.) D 63 M MCPA, bromoxynil (p.o.) Paracetamol D 37 M MCPA, bromoxynil (p.o.) D 77 F Bromoxynil (p.o.)a D 35 M MCPA, bromoxynil (p.o.) A 56 M MCPA, bromoxynil (p.o.) Dimethoate, dicamba, A 50 F MCPA, bromoxynil (p.o.) A 60 M MCPA, bromoxynil (p.o.) A p.o. route: oral administration; i.v. route: intravenous. aMCPA was detected in the blood of these patients.

Table 2. Fatal cases of bromoxynil ± MCPA ingestionsa.

Age Sex Toxin Others Bromoxynil MCPA Time of death concentration concentration 78 M MCPA 221 mg/L 156.5 mg/L 7h post admission Bromoxynil 37 M MCPA 137 mg/L 83.9 mg/L 20 h post ingestion Bromoxynil 26 M MCPA 1.9 mg/kg 184 mg/kg 30 h post ingestion Bromoxynil 63 M MCPA Paracetamol Detected in Detected in 12 h post admission Bromoxynil urine urine 53 F Bromoxynila Bromadiolone, 140 mg/kg 37 mg/kga 17 h post ingestion glyphosate 77 F Bromoxynila 104.3 mg/L 41 mg/La 23 h post ingestion 70 F MCPA Not done 10 h post admission Dicamba 46 M MCPA 61.5 mg/L Seven days post Moxidectin ingestion aTwo patients did not report taking MCPA but it was detected in the blood toxidrome, six had apparently taken bromoxynil with MCPA, with one of these also taking glyphosate and bromadiolone. Note this includes the two that did not report MCPA co-ingestion. There were two fatalities that were related to MCPA and dicamba or moxidectin co-ingestion (Tables 1 and 2). One patient had the same toxidrome and one died on day 7 from MCPA and moxidectin ingestion, after severe rhabdomyolysis and acute renal failure. Discrepancy between the laboratory assays and patients reports suggest that history may be inaccurate. It was important to be able to perform laboratory assays to ascertain the pesticides causing death.

In conclusion, our case series showed that 6/14 patients died from MCPAþbromoxynil while 2/8 patients died from MCPAþother herbicide poisoning, we postulate the former combination is more toxic and could be a potentially lethal combination.

A limitation of this study was the small number of patients who had bromoxynil and/or MCPA poisoning. More than one herbicide was ingested in every case and it is difficult to determine their relative contribution towards the toxicity. However, there are few reported bromoxynil and MCPA poisoning cases and this case series highlights the frequently lethal toxicity.

Disclosure statement

No potential conflict of interest was reported by the authors.

ORCID

Angela L. Chiew http://orcid.org/0000-0002-0079-5056

Nicholas A. Buckley http://orcid.org/0000-0002-6326-4711

References

[1] Chiew AL, Page CB, Clancy D, et al. 2-methyl-4-chlorophenoxyacetic acid (MCPA) and bromoxynil herbicide ingestion. Clin Toxicol. 017;1–4.

[2] Bradberry SM, Watt BE, Proudfoot AT, et al. Mechanisms of toxicity, clinical features, and management of acute poisoning: a review. J Toxicol Clin Toxicol. 2000; 38:111–122.

[3] Roberts DM, Seneviratne R, Mohammed F, et al. Intentional selfpoisoning with the chlorophenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA). Ann Emerg Med. 2005;46:275–284.

[4] Flanagan RJ, Meredith TJ, Ruprah M, et al. Alkaline diuresis for acute poisoning with chlorophenoxy herbicides and ioxynil. Lancet. 1990;335:454–458. [5] Berling I, Buckley NA, Mostafa A, et al. 2-Methyl-4-chlorophenoxyacetic acid and bromoxynil herbicide death. Clin Toxicol. 2015;53:486–488.

Betty S. H. Chan and Angela L. Chiew

NSW Poisons Information Centre, Children’s Hospital Westmead, New South Wales, Australia Toxicology Unit, Prince of Wales Hospital, Sydney, New South Wales, Australia

[email protected] Q3

Sarah Grainger

Emergency Department, Ipswich Hospital, Queensland, Australia

Colin B. Page

NSW Poisons Information Centre, Children’s Hospital Westmead, New South Wales, Australia Toxicology Unit, Prince Alexandra Hospital, Queensland, Australia

Alan Gault

NSW Poisons Information Centre, Children’s Hospital Westmead, New South Wales, Australia Emergency Department, Queen Elizabeth II Hospital, Western Australia, Australia

Ahmed Mostafa

School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia