Herbicides and antibiotic resistance

A recent two-year study of the sub-lethal effects of three of the most commonly used herbicides has revealed some disturbing findings with regard to antibiotic resistance. One of the co-authors of the study, Jack Heinemann, explains.

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A WEED is any plant growing where it is not wanted. Commercial herbicides are sold to kill weeds. That sounds simple, but it isn't.

Herbicides are composed of a variety of different chemicals. The most often named is the so-called 'active ingredient'. This compound is the key to the efficacy of the herbicide. However, it does not act alone. The active ingredient must be able to both be delivered to the target plants and gain access to targets within the plant. This requires surfactants and other adjuvants to make the herbicide practical to use.

Each of the ingredients used in herbicides has the potential to cause harm to organisms that are not the herbicides' intended targets. Full knowledge of these harms informs government regulators who then issue decisions on if, how and for what purpose a herbicide can be used. But have they been operating with complete knowledge?

Probably not. Only this year we released results of a two-year study on the sub-lethal effects of three commercial herbicide formulations on bacteria (Kurenbach et al., 2015). All three formulations caused a previously unsuspected effect on both species of bacteria that were tested. The effect was that the bacteria uniformly responded by demonstrating a change in their ability to survive exposure to other kinds of toxins - those we use in clinical and veterinary medicine and which we call antibiotics.

The three herbicides were Roundup, Kamba and 2,4-D. The active ingredients of these herbicides are glyphosate, dicamba and 2,4-dichlorophenoxyacetic acid, respectively. These three herbicides are among the most used in the world, with glyphosate-based herbicides clearly No. 1. They are used in agriculture, but also in public spaces, sports fields and in home gardens.

The bacteria we used belong to species that cause disease in people and animals. They were Salmonella enterica and Escherichia coli. The bacteria responded according to some species-specific differences to the different herbicides and antibiotics. Frequently, they demonstrated an increase in resistance to the antibiotics we tested. Occasionally there was no response or an increase in sensitivity to the antibiotic. It would be premature to assume that an increase in sensitivity would have a beneficial effect; we are testing that now.

An increase in resistance is an observation to take seriously because the effectiveness of antibiotics is declining. Even relatively small increments in resistance can undermine treatment (Figure 1). For example, one study found that a two-fold change in resistance of infecting bacteria was enough to cause 21% of patients to get a lower-than-target dose of the recommended antibiotic. And when the resistance reached a four-fold increase, 75% of patients failed to receive the target dose (Haeseker et al., 2013). The effect we measured caused changes between two- and six-fold.

The effect required exposure to a more concentrated source of herbicide than is generally legally allowed on food, e.g., the 'maximum residue limits' set by Codex Alimentarius. However, much less herbicide than is allowed to be applied to plants causes the effect. Therefore, potentially farmers but especially farm animals exposed through spray drift or feed they consume on-farm could have these levels of herbicide. Insects such as pollinators can be exposed to these levels. In cities, children and pets may be exposed as they unwittingly walk in or play on treated lawns and gardens. All of these unintended exposures are in people and animals that routinely receive antibiotics to control disease.

Even when people and animals are not directly exposed to the herbicide, people and animals may be exposed to bacteria after they were directly exposed. For example, in some countries antibiotic use in farm animals is so high that the antibiotics are detected in manure. This manure is also spread on fields as fertiliser, where it may also come into contact with herbicide. This is the mix that results in the resistance response. Other research has shown that insects such as flies that visit the manure can acquire the bacteria, potentially transferring them (Zurek and Ghosh, 2014).

Exposure to herbicides via the mouth, called ingestion exposure, is not limited to eating food. There can be non-dietary ingestion of herbicide. For example, our hands may be exposed to multiples of the residue found on different products through handling food during harvest or preparation. This may cause a 'from hand to mouth' pathway for exposures to higher levels of herbicide. We are uncertain about how high skin concentrations can be. That is why we imagine that pets would be an important potential vector to study. They conceivably are exposed to application rate concentrations of herbicide when they roam through recently treated lawns or gardens and then may transfer the herbicide to the hands or face of those who stroke the pet.

Our study also found that combinations of different products (e.g., Kamba + aspirin) had an additive effect. It is likely that other chemical exposures can also combine with herbicides to cause the effect. This effectively lowers how much herbicide is needed to cause the effect.

The additive effect of aspirin has some irony. Aspirin is acetylsalicylic acid, or more generally a salicylate. These compounds have long been used in some kinds of agriculture as 'safeners', compounds added to desirable plants to lessen the toxicity of herbicides. Daniel Goldstein1 of Monsanto referred to glyphosate (although not Roundup) as no more toxic than aspirin.2 Others have also made this particular comparison (Duke and Powles, 2008).

Why is this ironic? In effect, the herbicide is also a safener. However, the effect of the herbicide is to reduce the toxicity of some antibiotics to bacteria.                                                          

Prof Jack Heinemann is with the Centre for Integrated Research in Biosafety (INBI) and the School of Biological Sciences at the University of Canterbury in New Zealand.

Endnotes

1. http://monsantoblog.com/2013/07/03/a-pediatricians-inside-monsanto/

2. See 'dagtox' comment under this article: http:/www.scientificamerican.com/article/weed-whacking-herbicide-p/

References

Duke, S.O. and S.B. Powles. 2008. 'Glyphosate: a once-in-a-century herbicide'. Pest Manag Sci 64, 319-325.

Haeseker, M., L. Stolk, F. Nieman, C. Hoebe, C. Neef, C. Bruggeman and A. Verbon. 2013. 'The ciprofloxacin target AUC : MIC ratio is not reached in hospitalized patients with the recommended dosing regimens'. Br J Clin Pharm 75, 180-185.

Kurenbach, B., D. Marjoshi, C. Amabile-Cuevas, G.C. Ferguson, W. Godsoe, P. Gibson and J.A. Heinemann. 2015. 'Sub-lethal exposure to commercial formulations of the herbicides dicamba, 2,4-D and glyphosate cause changes in antibiotic susceptibility in Escherichia coli and Salmonella enterica serovar Typhimurium'. mBIO in press, 9-15. DOI 10.1128/mBio.00009-15

Zurek, L. and A. Ghosh. 2014. 'Insects represent a link between food animal farms and the urban environment for antibiotic resistance traits'. Appl Environ Microbiol 80, 3562-3567.

*Third World Resurgence No. 295, March 2015, pp 23-24