The ADI study for Europe, Australia & Canada: The original research showing glyphosate causes Leydig cell tumours in rats.

P1060019_2This is the Monsanto funded study that advises the ‘no observable effect level’, more simply known as the safe level for glyphosate, which enables the European Commission to then establish the Acceptable Daily Intake (ADI) for Europe – the ADI is the level of pesticide that is considered safe to us consume on a daily basis for our lifetime.

It was first inserted in the 1986 WHO JMPR evaluations. 18 years later, the European Commission keep using this private, outdated Monsanto study – listed under:

Review report for the active substance glyphosate 6511/VI/99-final

The Lankas study cannot be referenced on the European Commission pages – they simply cite an ADI of 0.3 mg/kg bw (page 13), based on the carcinogenicity studies a 2 year rat test with a NOAEL of 31 mg/kg bw/day (page 12).

It’s hard to track down.

These European Commission reports are terrible for researchers attempting to understand who authored and paid for the actual studies  – however it can be cross referenced with the WHO 2004 Part II Toxicological Evaluations of glyphosate – page 95 – ‘was last evaluated by the JMPR in 1986, when an acceptable daily intake (ADI) of 0– 0.3mg/kg bw was established based on a no-observed-adverse-effect level (NOAEL) of 31 mg/kg bw per day, the highest dose tested in a 26-month study of toxicity in rats.’  Records are also held on the IPSC INCHEM website – 1986 data gives Lankas 1981.

This study was also established in 1986, as the NOAEL for the WHO and the USA.  Later on the USA changed to a much higher NOAEL with this Monsanto study.

In 2004 the FAO/WHO Toxicological Evaluations, see page 160, dismissing lower NOAELs showing harm, used another study by Cheminova, Atkinson 1993b*, to increase the NOAEL and hence the ADI.

The Lankas study remains the base NOAEL limit to establish the lower ADI for (at a minimum) Europe, Australia, New Zealand and Canada.

Lankas 1981

A Lifetime Feeding Study of Glyphosate (Roundup Technical) in Rats Groups of 50 male and 50 female Charles River Sprague-Dawley rats were fed technical glyphosate in their diets at dose levels of 3, 10,or 31 mg/kg b.w./day (males) and 3.4, 11, or 34 mg/kg b.w./day(females) for approximately 26 months. Animals were observed twice daily for clinical signs and mortality. Body weights and food consumption were determined intitially, weekly to 14 weeks, and biweekly thereafter. Blood and urine were collected from 10 animals/sex /group at 4, 8, 12, 18, and 24 months. Full haematological and clinical chemical determinations and urinalyses were performed on those samples. All animals were subjected to gross pathological and histopathological examinations. There were no clinical signs of toxicity and no effects of treatment on mortality. There were no treatment-related effects on body weight at the end of the study, but there was a consistent tendency for reduced body weights in treated males during most of the growth period. Haematology, blood chemistry, and urinalysis were unremarkable. There were no treatment-related effects on organ weight and no remarkable findings at gross necropsy or after histopatho-logical examination. There were no increases in tumours that were treatment related. The incidence of interstitial cell tumours of the testes was slightly high in the high-dose group (control, 0/15; low-dose, 2/26; mid-dose, 1/16; high-dose, 4/26). However, this tumour is common in aged rats and the incidence was not above historical control levels. The no-observed-effect level exceeded 31 mg/kg b.w./day in the diet (Lankas, 1981).

Extract from Inchem WHO/FAO Pesticide Residues in food – Part II Toxicological 1986 Evaluations.

Lankas, G.R.; Hogan, G.K. (1981) A Lifetime Feeding Study of Glyphosate (Roundup Technical) in Rats: Project No. 772062. (Unpublished study received Jan 20, 1982 under 524-308; prepared by Bio/dynamics, Inc., submitted by Monsanto Co., Washington, D.C.; CDL:246617-A; 246618; 246619; 246620; 246621).  MRID 00093879   Please note that Leydig cell tumour is a very rare cancer.

Yet with climbing application rates of Roundup on our cereals, Lankas 1981 may be a good study to keep in mind for ongoing reference purposes.

Safe Says Who Questions and Comments:

 

In the high dose level:  4/26 rates had interstitial cell tumours of the testes, otherwise known as Leydig cell tumours.   That is a 15% rate of tumour.  This was dismissed as being a common tumour in aged rats and not above historical control levels. The Sprague-Dawley rat, the Leydig cell tumour is frequently found in older rats, with a background incidence of 1-5%. [1]  So I postulate that the tumour rate in this study was higher than normal. The fact is, however, that the particular breed of rat they used is about as prone to developing tumours as humans living in industrialized countries. Researchers view it as an excellent human-equivalent model for tumour-causing and cancer-causing effects [2].

Please note that the EPA, WHO or EU never test for reproductive or developmental carcinogenicity (in studies supplied to the toxicity agencies EPA/WHO/EFSA) using the stronger formulation of Roundup that is applied to our crops.  Pure glyphosate, as used in this study isn’t as potent.

  • This is a study for carcinogenicity. The rats developed tumours at the highest dose.  The declared the safe level, the NOEL, at the very same dose.  This is a significant study that decides the ADI for Europe.  How could they declare the safe level at the same level that 15% of the population developed tumours (three times higher than the background incidence)?
  • The study authors dismissed the results because the rats were aged.  Isn’t that the point?  A lifetime test should assess carcinogenicity from long term use?
  • What was the tumour rate at younger ages?  We don’t know because they only tested older rats.
  • Why do they say that “There were no increases in tumours that were treatment related” when tumours increase with the highest dose?
  • Why would a 15% tumour rate be dismissed as normal?
  • What are the ‘historical controls’ they are basing this decision against?
  • Has the relative sensitivity between the rat and human Leydig cells in their response to increased LH levels ever been studied?

This is a Monsanto funded study that determines the level of safety for glyphosate and therefore Roundup for the citizens of the European Union, Australia, Canada, New Zealand and many other countries.  A critical study.

But if we want to look further into this particular study, we cannot, as on 12 December 2012 a court in Braunschweig, Germany ruled  that there is no public interest reason to publish the original industry toxicity studies on glyphosate, the active ingredient in Roundup herbicide, on which the EU approval of glyphosate is based. No independent scientist acting in the interests of public health can investigate the ‘historical controls’ that enabled the Monsanto- paid study authors to dismiss what may be a significant tumour rate for a carcinogenicity study.

Further reading: From Toxicological Risk Assessment of Chemicals: A Practical Guide (2008):  There are plausible mechanisms (non-genotoxic) for the chemical induction of Leydig cell tumours: most of these ultimately involve increased concentration of serum LH (luteinising hormone) and associated stimulation of Leydig cells to growth and proliferation, or an increased sensitivity to LH in the Leydig cells.  Regarding human relevance, the pathways for regulation of the hypothalamic-pituitary-testis (HPT) axis of rats and humans are similar and the mechanism is relevant for humans.  Hence chemicals that induce Leydig cell tumours in rats by disruption of the HPT axis pose a cancer risk to humans.  Therefore the central issue becomes what is the relative sensitivity between the rat and human Leydig cells in their response to increased LH levels. There is evidence suggesting that human Leydig cells are quantitively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induces Leydig cell tumours.  Men suffering from endocrine diseases, which cause a constantly increased LH level, develop Leydig cell adenomas with a frequency of 2-3%.  (End extract)  [1]

A recent  study has demonstrated that the HPT axis in perinatally exposed rats can be disrupted by glyphosate. [3] Romano et al. demonstrated that glyphosate can increase the mRNA expression and protein content in the pituitary gland and the serum concentration of LH.  [4] And here is an extract from a recent study, albeit using rats dosed with three different agrichemicals: In this sub-clinical study with agri-chemicals, treated (ZGD) Wistar rats injected i.p. with a combination of 15 mg dimethoate (D)/kg of body weight (bw), 15 mg zineb (Z) /kg bw and 10 mg glyphosate (G)/ kg bw dissolved in PEG-400, three times a week for five weeks. Discussion:  Results reported in the present study showed that, the mixture of the most frequently used agrochemicals administered at very low doses produced significant detrimental effects on both the spermatozoa characteristics and functional parameters.  Both types of oxidative stress biomarkers – enzymatic and nonenzymatic- were severely altered in plasma and testis indicating a significant unbalance between free radical production and antioxidant defenses. Plasma hormonal levels were also altered. Free and bound testosterone, as well as estradiol levels were depressed in plasma from treated rats while LH and FSH content were increased compared to controls. These results could be interpreted as an adaptative feed-back response of the gonadal-pituitary (HPG) axis induced by the decay of testosterone level.   [5]  

Food Standards New Zealand advises that the New Zealand ADI for glyphosate is 0-1.0mg/kg – a higher daily level, based on the WHO level. This was changed in 2011 (the MRL team advises following the WHO JMPR 2011 Toxicity Evaluation).

The WHO glyphosate ADI glyphosate re-evaluation from 0.3mg/kg up to 1.0mg/kg was earlier, set as a recommendation during the 2004 FAO JMPR toxicological evaluations . P.160.:
‘The Joint Meeting established a group ADI for glyphosate and AMPA of 0–1.0mg/kg bw on the basis of the NOAEL of 100mg/kgbw per day for salivary gland alterations in a long-term study of toxicity and carcinogenicity in rats and a safety factor of 100. The ADI is supported by NOAELs of 141 and 197mg/kgbw per day from the 1-year study and the two-generation study of reproductive toxicity in rats, respectively.’

The Australian APVMA (as of 2013) advises it retains the lower European .3mg/kg ADI.

 

How to fix it – demand transparency when pesticides are evaluated for toxicity.

 

References:

*  Atkinson, C., Strutt, A.V., Henderson, W., Finch, J. & Hudson, P. (1993b) Glyphosate: 104 week combined chronic feeding/oncogenicity study in rats with 52 week interim kill (results after 104 weeks.). Unpublished report No. 7867, IRI project No. 438623, dated 7 April 1993, from Inveresk Research International, Tranent, Scotland. Submitted to WHO by Cheminova A/S, Lemvig, Denmark.

[1] Toxicological Risk Assessment of Chemicals: A Practical Guide. 2008.  By Elsa Nielsen, Grete Ostergaard, John Christian Larsen ISBN-10: 0849372658, ISBN-13: 978-0849372650 [2] Soffritti M, Belpoggi F, Degli Esposti D.

[2]Cancer prevention: The lesson from the lab. In: Biasco G, Tanneberger S, eds. Cancer Medicine at the Dawn of the 21st Century: The view from Bologna. Bologna: Bononia University Press; 2006:49–64.

[3] Kizys, MML; Sena-Souza, J; Romano, RM; Frossard, MM; Ortiga-Carvalho, TM; Maciel, RMB; Giannocco; Dias-da-Silva, MR; Romano MA.  Hypothalmus-pituitary-thyroid axis in perinatally exposed rats can be disrupted by a largely used broad-spectrum herbicide – glyphosate.

[4]  Romano MA, et al.  Glyphosate impairs male offspring reproductive development by disrupting gonadotropin expression.   Arch Toxicol. 2012 Apr;86(4):663-73. doi: 10.1007/s00204-011-0788-9. Epub 2011 Nov 26. [5]  Hurtado de Catalfo Graciela, Astiz Mariana, Alaniz María J. T. de and Marra Carlos Alberto.  Frequently-used agrochemicals lead to functional and morphological spermatozoa alterations in rats.  Journal of Toxicology and Environmental Health Sciences Vol. 3(7) pp. 180-192, July 2011.  ISSN 2006-9820 ©2011 Academic Journals

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