Paraquat’s ‘safety measure’ based on flawed research, a review of over 30 studies shows

New analysis from the Centre for Pesticide Suicide Prevention (CPSP) has shown that the dose of vomiting agent included in standard paraquat products is based on flawed evidence.

Paraquat, often known by its original brand name Gramoxone, is one of the most commonly used herbicides worldwide. It is also highly poisonous and fatal to humans when ingested.

Following a series of deaths due to unintentional ingestion, often a result of paraquat being decanted into drinks bottles, a vomiting agent named PP796 was added to standard paraquat products in the 1970s.

The concentration of 0.05% was selected by the manufacturer. It claimed this was an effective dose for inducing vomiting and preventing deaths, based on scientific evidence.

CPSP has conducted a systematic review of over 30 studies. This has exposed issues with the manufacturer’s data. It also found no evidence that the current dose of PP796 helps to save lives.

Examination of unpublished company reports

The new study aimed to identify the evidence that drove the use of PP796 and suggested it was effective in preventing deaths.

It included a review of unpublished clinical and pre-clinical research, undertaken by the manufacturer, that were done as part of the development process. These documents have only been made public over the last few years as a result of court cases in the USA.

The company documents were examined alongside published literature on the dose and effectiveness of PP796 in different paraquat products.

Inadequate research and flawed datasets

The review found that PP796 was selected as a vomiting agent on the basis of a single inadequate human study involving just 12 volunteers. The trial tested seven dose levels, with 1-3 volunteers receiving each dose.

Less than half of all participants involved in the study vomited within 30 minutes. The only participant to receive the highest dose showed no sign of nausea or vomiting in this time frame.

Further animal studies indicated that a dose of at least 0.5-2 mg/kg was needed for PP796 to be effective, with higher doses inducing more rapid vomiting. However, a lower dose of 0.05% PP796 (equivalent to 0.071 mg/kg in a 70 kg adult) was selected by the manufacturer.

The manufacturer justified this lower dose with claims that humans are more sensitive to PP796, despite no primary data and no mechanistic explanation to suggest this is the case.

The lower dose was based on evidence from the earlier human study. However, instead of using data from all 12 volunteers (which is already too small a study), the manufacturer’s decision was based on results from only five volunteers across three dose levels.

The report replaced the three volunteers who received a dose of 0.03 mg/kg with data from 37 patients participating in a separate clinical trial. This produced a flawed dataset.

Inaccurate claims influence international specifications

These errors in data interpretation allowed the manufacturer to make unsubstantiated claims regarding the effectiveness of PP796 as a vomiting agent in paraquat products.

The Food and Agricultural Organization (FAO) subsequently adopted the manufacturer’s recommended dose as its international specification. This includes a requirement for more than 50% of patients to vomit within 30 minutes, although this recommendation was based on no evidence.

The naming of PP796 in the specification appears to have given the company a commercial advantage, allowing it to sell its patented PP796 product to other companies who wished to manufacture paraquat.

To date, no primary pre-clinical or clinical data have been published regarding PP796’s effectiveness.

A highly dangerous product

The review was conducted by Professor Michael Eddleston, Director of the Centre for Pesticide Suicide Prevention and Professor of Clinical Toxicology at the University of Edinburgh, who said:

“The international specification for paraquat products has remained the same for over 30 years, requiring incorporation of a compound able to cause vomiting within 30 minutes. However, our review has clearly shown that there has never been any robust evidence to support this recommendation.

The evidence put forward by the manufacturer in the 1970s was significantly flawed. Data were selected from different studies to produce a simplified result. The dose of PP796 chosen, which is still the same dose used in paraquat products today, is almost certainly unable to improve the outcome of poisoning.

Paraquat remains highly dangerous. Products containing this ineffective 0.05% dose of PP796 should not be permitted for use by small-scale farmers who are at high risk of death from poisoning.”

The review is published in Clinical Toxicology.