Nitrate: a Public Health Hazard?
Human Health and Antibiotic Growth Promotors (AGPs): Reassessing the Risk

complete rapport

Nitrate: a Public Health Hazard?

The presence of nitrate (NO3-) in food and drinking water is considered a major public health problem. In the Netherlands the maximum nitrate concentration in drinking water is 50 mg NO3- per litre. If this standard is exceeded, the water is considered unsafe. Maximum allowable nitrate concentrations have also been set for food, including vegetables and meat; these are given in the Commodities Act.

In his report 'Nitrate and Public Health: an Overview' J.C. Hanekamp investigates the extent to which nitrate actually forms a public health hazard. The standard set for the nitrate concentration in drinking water is subjected to a critical analysis in this report.

The report is part of a more comprehensive study into the environmental and health effects of phosphate and nitrogen compounds (including nitrate) which the 'Heidelberg Appeal Nederland' Foundation is carrying out at the request of the 'Nederlandse Vakbond Varkenshouders' (NVV; Netherlands Pig Keepers Trade Union). The present report focuses exclusively on any public health effects and risks related to nitrate; other environmental effects will be discussed at a later stage.

Two  main types of public health risk due to nitrate exposure are distinguished

• acute (direct) effects (in casu methaemoglobinaemia)
• chronic (long-term) effects (in casu gastro-intestinal cancers)

First of all it should be noted that the toxicity of nitrate is in fact caused primarily by nitrite formed in the body. Nitrate itself is practically non-toxic apart from the disruption of the osmotic and electrolytic balance in stomach and intestines inherently caused by salts. The nitrite formed can oxidise haemoglobin to methaemoglobin resulting in methaemoglobinaemia. This serious and very rare metabolic disorder is clinically diagnosed as such at a methaemoglobin concentration of at least 10%. Above a certain concentration level the organism may be harmed by oxygen deficiency. In the most serious case this leads to death -this occurs at methaemoglobin levels of between 45% and 60%. New-borns are most susceptible to methaemoglobin formation. Adults in general are highly insensitive to nitrate.

In 1945 a study was published that dealt with acute nitrate poisoning in infants. This study established a relationship between the consumption of drinking water with a high nitrate content and methaemoglobinaemia. (As stated, under certain conditions nitrate is converted into nitrite in the body). However, later studies proved that methaemoglobinaemia is most probably caused by gastro-intestinal infections. The immune response to the gastro-intestinal infection causes a higher nitrate level in the body due to the endogenous nitrate production. This nitrate may be reduced to nitrite in the intestines by the infectious bacteria present there, and this may result in methaemoglobinaemia. In effect the children fall victim of their own immune response to the infection.

The long-term effect of nitrate exposure has been subject of many scientific studies. Extensive epidemiological studies, however, have not yielded a causal association between chronic nitrate exposure and an increased risk of gastric and/or intestinal cancer or other types of cancer. Even long-term exposure to relatively high nitrate doses is not known to cause any health problems. This was found, inter alia, in studies among groups of people professionally exposed to high nitrate doses (namely male workers of fertiliser plants).

Hanekamp concludes that from a public health point of view concern about the nitrate content of drinking water and food is not justified. The current levels do not present any public health hazard. Adults are quite insensitive to nitrate exposure. It can be concluded that the present drinking water standard for nitrate can at most serve to protect infants with gastro-intestinal infections.

Emergence of a debate: AGPs and Public Health
Human Health and Antibiotic Growth Promotors (AGPs): Reassessing the Risk

Executive Summary and Conclusions   (complete rapport)

Introuduction

The question has been raised whether the use of antimicrobial growth promoters (AGPs) in animals can result in resistance within human bacteria. Transfer of resistance to antibiotics from livestock to humans is the point of concern here. The question is whether or not this implies a threat to human health. FEFANA (Fédération Européenne des Fabricants d'Adjuvants pour la Nutrition Animale: European federation of feed additive producers) asked the HAN foundation to re-evaluate the risk associated with the use of antimicrobial (antibiotic) growth promoting agents in livestock feed in relation to public health.

In a simplified manner, the risk issue concerning AGP use and human health can be depicted as follows, keeping in mind that any type of use ('presence') of antibiotics will result in the rise of resistant bacteria, in the species in which it is being used:

Figure 1. Possible sources of human bacterial antibiotics resistance.

The risk assessment thus revolves around the question to what extent, if at all, the use of AGPs in animal rearing contributes to bacterial antibiotic resistance already present in humans.

The Data

A prerequisite in this hazard scheme is the transfer of animal bacterial antibiotic resistance from animals to humans. A risk assessment thus in part requires data concerning this resistance transfer. Unfortunately, these data are in essence non-existent. Van den Bogaard et al. (1997b) claimed that a turkey and a farmer had the same strain of vancomycin-resistant E. faecium. Until now this letter is the only one that describes indistinguishable strains in animals and humans suggesting a possible transfer of bacteria. However, it was not proved that this strain really colonised the human gut. Furthermore, since other reports describing similar cases are not available, reproducibility is absent. Generalisation from this particular observation is scientifically unsound and without foundation as transfer mechanisms of DNA are manifold taking into account the different bacteria species and genera and the several resistant traits of interest.

Resistance transfer -although crucial- is, however, only part of the total risk assessment process. The acquiring of resistance by micro-organisms under selective antibiotics pressure is far from uniform and in many cases not fully resolved. Furthermore, the epidemiological consequences of resistance transfer from animals to humans, once established in a reproducible manner, need to be taken into account. Epidemiological data to this date do not show that use of AGPs in animal rearing compromised the use of related antibiotics in human medicine. Therefore, past experiences do not reveal that AGPs are a major source of resistance within human bacteria even after 30 years of use. Moreover, there are no indications that human infectious diseases are on the increase as a result of the use of AGPs. Risk analysis also requires the positive (health) effects to be taken into account such as improved animal welfare and the reduction of the shedding of pathogenic zoonotic micro-organisms.

It is clear that reproducible and documented data concerning antibiotic resistance transfer from animals to humans is lacking. This makes a formal risk assessment of this issue not possible. By definition risk assessment can not be based only on the possibility (the hazard identification) that antibiotic resistance could in theory be transferred from animals to humans. A quantitative scientific basis is needed for that. Risk analysis guarantees that sound scientific data are applied in weighing both the positive- against the negative health effects.

In Conclusion

• The human health risk concerning the use of AGPs cannot be properly assessed for lack of data.
• The contribution to human bacterial antibiotic resistance from animal bacterial resistant cannot be fully assessed for lack of data.
• Sofar, AGP use did not compromise the human therapeutic use of related antibiotics.
• Sofar, epidemiological data do not show an increase of infectious diseases as a result of the use of AGPs.
• Thorough documented in vivo cases showing the spread of antimicrobial resistant Gram-positive bacteria from livestock to humans are in essence non-existent.
• Resistance transfer from animals to humans is only part of the entire risk chain. The major parts of this chain of events comprise of a micro-biological/ genetic part, an animal-human transfer part and an epidemiological part.
• Assessing the human health risk in relation to AGPs involves making a full scientific inventory. Beneficial aspects such as animal welfare in relation to the use of AGPs and the influence of AGPs on the spread of pathogenic zoonotic organisms also need to be taken into consideration.
• A comprehensive multidisciplinary research effort is needed to properly assess all aspects of the use of AGPs in animal husbandry.