Researchers on Drugs

Sensitive zucchini are the topic of this month’s library. More specifically, hormones in zucchini plants. Even more specifically, yet another study where researchers used spike solutions of pharmaceutical compounds (in this case the anticonvulsive carbamazepine and the high blood pressure medication verapimal) at unrealistically high concentrations added to soils and measured uptake by plants. These results were then used to sound the alarm bells for the safety of land application of biosolids. This has become a tried and true practice to get publications in Environmental Science and Technology, an otherwise well respected and competitive journal (see previous libraries, specifically March 2014 and September 2010).

For the first article in the library, the authors added each drug to soil at concentrations ranging from 0.005 to10 ppm and measured plant response in zucchini. When soil concentrations of carbamazepine were greater than 4 ppm the leaf tissue of the plants showed burnt edges and white spots. No effects were observed for the verapimal. The authors studied plants further and found changes in the plant hormonal balances and increased nutrient concentrations with soil carbamazepine concentrations greater than or equal to 4 ppm.

The data reported in this article on hormone concentrations look like a mess to me. For example, concentrations of abcisic acid were highest in the control and lowest for the plants treated with verapimal, much lower than for carbamazepine. At the high doses of carbamazepine, the abcisic acid concentrations were similar to the control. Concentrations of auxins were higher in the verapimal-treated soils compared with the control. They were also higher than the control in the carbamazepine-treated soils, for some of the lower treatments, but not at the high treatments. To me, this is an example of statistics telling you something that does not follow any reasonable pattern or make sense. The authors admit that there is little likelihood that this uptake could or would impact humans, but conclude it could affect plant growth.

Just for a point of reference here, the authors use unnaturally high concentrations of these medications. The lowest therapeutic dose of carbamazepine is 200 mg per day (paper #5). An acceptable daily intake is 2.9 g kg-1 (#5). For a person weighing 60 kg, that comes to 175 g per day or 0.175 mg, a little less than 1000 x the lowest daily dose. A paper from an earlier library measured concentrations of carbamazepine in biosolids from a treatment plant in New Hampshire at 258 g kg-1 or 0.3 ppm. In other words, the concentrations of the spiked soil, where an impact was observed in the first study, were an order of magnitude higher than concentrations in pure biosolids. Not only were no biosolids used in the study (a factor that, in itself, can greatly impact plant availability of a compound), the addition rate did not take into account normal biosolids loading rates.

None of that “dose of reality” impacted the author or the 2nd paper, nor apparently the scientist that she quotes extensively in the article. The article starts with a picture of two humongous zucchini that were not from the study. As anyone who has grown zucchini can attest, this is normal zucchini in August when you neglect to pick your zucchini every hour. She quotes Chris Higgins from the Colorado School of Mines basically saying that biosolids are a mysterious toxic brew of pharmaceuticals that need close monitoring and attention. Chris was asked to please justify his comments. So far silence.

For the third paper, we go to Kuldip Kumar from the Chicago biosolids program. Here Kuldip and his co-author have develop a rule of three to predict which pharmaceuticals are likely to be taken up by plants. This rule of three says that you need to look at the molecular weight of the compound, then look at how hydrophobic it is (octanol water partition coefficient or Kow) and finally look at how many hydrogen ions it can donate or take. Lower numbers of hydrogen donors (<3) and acceptors (<6), a molecular weight <300 and a log Kow <3 suggest a high potential for plant uptake.

So let’s use Kuldip’s rule of three for carbamazepine:

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Looks like this drug is highly likely for plant uptake: low molecular weight, low Log Kow and only two sites for H donation or acceptance. Kuldip cites a few papers with plant uptake, but these are based on salts, not biosolids. How about we look to see if any studies have actually shown plant uptake of carbamazepine from real-life biosolids-amended soils?

Prior libraries have featured articles where no uptake has been observed. Here I am thinking of work by Ed Topp’s group in Canada, where his lab saw no uptake of pharmaceuticals in wheat or garden vegetables grown in biosolids amended soils. I found a paper by Chad Kinney where they grew cabbage in both spiked soil and soil with biosolids (#4). Biosolids were added to soils at 2% dry weight, or about 20 tons per acre, not quite agronomic rates but not terribly high. The final soil/ biosolids mixture had 93 ng g-1 concentrations of carbamazepine or 0.09 ppm. The carbamazepine concentration in the biosolids used was not reported, but if you figure a 50 x dilution that would mean that the biosolids had 4.5 ppm carbamazepine, a lot higher than that previous study out of New Hampshire. Also, this is a lot higher than a previous survey paper by Kinney et al. (2006). The results of that survey are shown below. The highest concentration they saw was 1.2 ppm with a median concentration of 0.068 ppm; just saying….

So, for this paper, Kinney found special biosolids and added them at the high end of reasonable rates. But, as Kuldip predicted, cabbage grown in that soil had leaf concentrations of carbamazepine of 255 ng g-1 or 0.3 ppm. This suggests that, in very special cases, plants can take carbamazepine up from biosolids-amended soils.

That leads us to the last paper in the library. This is a recent human health risk assessment on consuming plants grown in biosolids-amended soils. The authors here conclude that the vast majority of the compounds looked at showed a hazard quotient of < 0.1, meaning no hazard. Carbamazepine was one of the few compounds tested where the hazard quotient was higher, at 0.2. However, the authors of this study note that the plant uptake values that they used in their hazard quotient were from studies where salts had been used and are likely not reflective of real world situations.

So, if you look at the combination of papers #4 and #5, you can eat up to 0.175 mg of carbamazepine a day. The Kinney cabbage had about 0.255 mg kg-1 carbamazepine. That would mean if you eat up to 1.5 lbs of cabbage every day from those special biosolids, you’ll still be OK.

Bring on the coleslaw!

Sally Brown, University of Washington