Abstract
Milk residues and performance were evaluated in lactating cows that were fed up to 10 times the recommended dose of monensin. Following an acclimatization period of 14 d, during which cows were fed a standard lactating cow total mixed ration containing 24 ppm monensin, 18 lactating Holstein dairy cows were grouped according to the level of feed intake and then randomly assigned within each group to 1 of 3 challenge rations delivering 72, 144, and 240 ppm monensin. Outcome measurements included individual cow daily feed intakes, daily milk production, body weights, and monensin residues in composite milk samples from each cow. There were no detectable monensin residues (< 0.005 μg/mL) in any of the milk samples collected. Lactating cows receiving a dose of 72 ppm monensin exhibited up to a 20% reduction in dry matter intake, and a 5% to 15% drop in milk production from the pre-challenge period. Cows receiving doses of 144 and 240 ppm monensin exhibited rapid decreases in feed intake of up to 50% by the 2nd d and milk production losses of up to 20% and 30%, respectively, within 4 d. Lactating cows receiving up to 4865 mg monensin per day had no detectable monensin residues (< 0.005 μg/mL) in any of the milk samples collected. Results of this study confirm that food products derived from lactating dairy cattle receiving monensin at recommended levels are safe for human consumption.
Résumé
La présence de résidus dans le lait et les performances de vaches en lactation ont été évaluées après avoir été nourries avec des aliments contenant jusqu’à 10 fois la dose recommandée de monensin. Suite à une période d’acclimatation de 14 j pendant laquelle les animaux ont reçu une ration mélangée standard pour vache laitière contenant 24 ppm de monensin, 18 vaches laitières de race Holstein ont été regroupées selon la quantité de nourriture ingérée et assignées au hasard à chacun des trois groupes recevant une ration test contenant 72, 144 et 240 ppm de monensin. On a mesuré pour chaque vache la consommation quotidienne de nourriture, la production quotidienne de lait, le poids corporel et la quantité résiduelle de monensin dans un échantillon de lait composite. Aucune résidu de monensin ne fut détecté (< 0,005 μg/mL) dans les échantillons de lait prélevés. Chez les vaches en lactation recevant 72 ppm de monensin on nota une réduction de 20 % de la prise de matière sèche, et une diminution de 5 à 15 % de la production laitière comparativement à la période pré-traitement. Les vaches recevant des doses de 144 et 240 ppm de monensin ont démontré une baisse rapide de la prise de nourriture allant jusqu’à 50 % lors de la deuxième journée et une baisse de production laitière, respectivement, de 20 et 30 % en moins de 4 j. Aucun résidu détectable (< 0,005 μg/mL) ne fut trouvé à partir de tous les échantillon de lait prélevés chez des vaches Holstein en lactation recevant jusqu’à 4865 mg de monensin par jour. Les résultats de cette étude confirment que les produits alimentaires provenant de vaches laitières recevant du monensin aux doses recommandées sont sécuritaires pour consommation humaine.
(Traduit par Docteur Serge Messier)
Introduction
Monensin is the most commonly used ruminant ionophore in the world. While monensin has been used in the beef industry for the past 3 decades to improve feed efficiency and control coccidiosis, monensin has only recently been approved for use in lactating dairy cattle (1). In Canada, a monensin product (Rumensin; Eli Lilly, Guelph, Ontario) in the form of a controlled release capsule (CRC) has been approved for use in dairy cattle as an aid in the prevention of subclinical ketosis when administered 2 to 4 wk prior to the expected calving date. Studies in dairy cattle have reported health benefits that include bloat prevention and a reduction in the incidence of subclinical and clinical ketosis, displaced abomasum, and retained placenta (2). Other potential advantages of the administration of monensin to lactating dairy cattle include improved energy metabolism, increased milk production, and altered milk components (1–3).
From a food safety perspective, summaries of several studies (4,5) and unpublished data (6) have determined monensin residue levels in food derived from animals for human consumption. Monensin was not found in milk in any of this research despite the use of highly sensitive assays (7). Among these studies, the 2 highest levels of monensin administered were 1125 (5) and 1274.4 mg/head per day (6). Although rare, occasional mixing errors at the feed mill with monensin may occur and it is important to understand the implications to both animal and human safety under these circumstances. A typical mixing error at the level of the feed mill is a 10 × error because of transposing a decimal place. A 3 × or 6 × error could be made at the farm level through a mistake in filling the total mixed ration (TMR) mixer, such as confusing a mineral premix for a concentrate.
Therefore, the objective of this study was to further assess monensin residues in milk and the corresponding level of performance of lactating cows when monensin was administered in the feed. In an attempt to better understand the margin of safety, monensin residues were evaluated in lactating dairy cattle receiving 3, 6, and 10 times the dosage of 24 ppm in the feed. The dose of 24 ppm was chosen since it is the maximum approved dose for lactating dairy cattle in Canada.
Materials and methods
Study animals
The study population consisted of 18 healthy, lactating Holstein cows. Sample size was based on a summary of previous studies on toxicity of monensin (6). In one study, where 0, 1, and 10 mg/kg body weight (BW) of monensin were administered, signs of toxicity, including reduced milk production and feed intake, were seen in all 8 animals dosed at 10 mg/kg BW (6). The current trial provided doses of monensin between 1 and 10 mg/kg BW. Thus to maximize the likelihood of useful findings but to minimize animal suffering, it was decided that a minimum of 6 animals per treatment group was likely to provide useful data. All animals were evenly distributed among the treatment groups. Animal care guidelines based on the Canadian Council on Animal Care (8) were used to ensure attention to animal welfare during this study.
All of the cows used in this study had 4 functional quarters and had a minimum daily milk production average of 33.4 kg during the week prior to study initiation. Each animal was housed separately in a box stall and was fed a standard lactating dairy cow TMR. Cows were milked twice daily in a milking parlour adjacent to the box stall facility. The remainder of the cows within the commercial herd used for this study were housed in a group freestall and each was fed the TMR recommended for a lactating cow. The base TMR used in the experiment was the same as that used for the rest of the herd. However, the individual box stall assignments were necessary to facilitate the collection of DMI data. The herd had 9 boxstalls available, so this trial was conducted in 2 replications with 9 cows (3 groups of 3 treatments) in each replication. Cows were fed once per day and feed was pushed up twice per day. All cows in the herd as in the trial were milked twice per day in the regular milking parlour (double 8 parallel).
Feed formulations and procedures
Ration formulation was based on recommendations according to the guidelines of the National Research Council Subcommittee on Dairy Cattle (7) and feed ingredients were proportioned to meet production demands. The TMR included corn silage, haylage, and a custom dairy pellet. The dairy pellet was formulated to deliver 0, 24, 72, 144, and 240 ppm monensin in the TMR on a dry matter basis.
All cows were acclimatized to a diet of pellets containing a TMR formulated to provide 24 ppm monensin in the complete diet for a period of 14 d (day −14 to day −1) prechallenge. Following the prechallenge period, cows were placed according to their level of feed intake into groups of 3. Within each group, animals were randomly assigned to 1 of 3 treatments: dairy pellets formulated to deliver 72 ppm monensin (group A), 144 ppm monensin (group B), and 240 ppm monensin (group C). Cows in each treatment group were fed their respective formulation for a period of 21 d (day 0 to day 20). A portable cattle scale was used to weigh each cow prior to the administration of treatments.
Individual feed consumption was recorded daily throughout the trial period by weighing feed issued and feed refused. When a cow, on a daily basis, consumed less than 75% of its prechallenge period average daily feed intake for 3 consecutive days, or consumed less than 50% of its pre-challenge period average daily feed intake for 1 d, the cow was deemed to have met “anorexia criteria.” Cows meeting the anorexia criteria were switched to an unmedicated TMR for the remainder of the trial period. Once anorexia criteria were met, cows that consumed less than 10% of their prechallenge period average daily feed intake for 3 consecutive days were deemed to have met the “cow removal criteria” and were euthanized.
Cows in this trial were observed twice at each milking, once at each feeding, and at one additional planned observation time daily during the study period in order to record any behavioral or health abnormalities. In addition, a trial monitor visited the farm daily to observe cows and to calculate and administer the withdrawal criteria.
Drug formulation and administration
A custom pellet containing 200 g/kg BW of monensin sodium was produced to create the supplement that provided the amount of monensin required to test the animals (24, 72, 144, and 240 ppm in the TMR). From each treatment batch of pellets, composite samples were collected for monensin analysis by high performance liquid chromatography (Elanco Chemistry Research, Greenfield, Indiana). Composite samples of the feed ingredients were assayed for nutrient content (Agri-Analysis, Stratford, Ontario).
Milk collection and analysis
A composite milk sample was collected once daily from each cow on days −14, 0, 1, 2, 5, 7, and 20. All milk samples were frozen and transported on dry ice to Elanco Chemistry Research for monensin analysis by high performance liquid chromatography (HPLC) (9). The method used has a limit of quantification of 0.005 mg/mL (5 ppb). All assays were run with both a positive and a negative control. The positive control concentration was set at 10 ppb.
Results
Monensin challenge
During the prechallenge period, when the TMR was formulated at 24 ppm monensin, cows were consuming monensin in the range of 253 to 697 mg/day. No significant differences existed between the 3 treatment groups prechallenge for either dry matter intake or milk production. On the 1st d of the challenge, cows in group A (72 ppm monensin) consumed between 1253 and 1741 mg of monensin, cows in group B (144 ppm monensin) consumed between 2206 and 3376 mg of monensin, and cows in group C (240 ppm monensin) consumed between 3463 and 4865 mg of monensin. Prechallenge body weights of the cows ranged from 500.0 kg to 731.8 kg with an average body weight of 570.7 kg. All feeds were within tolerance (± 25%) for analyzed drug and nutrient content.
Of the 6 cows in group A, 1 cow reached anorexia criteria and was removed from the study on day 7 and another on day 13, the remaining 4 cows continued to receive monensin until the end of the trial (day 20). The mean number of days of monensin challenge for group A cows was 17.7 d, with a range of 8 to 21 d. Among group B cows, 1 reached anorexia criteria on day 2, 3 on day 3, and 2 on day 4. The mean number of days of monensin challenge for group B cows was 4.2 d, with a range of 3 to 5 d. For group C cows, 3 met anorexia criteria on day 1, 2 on day 2, and 1 cow on day 3. The mean number of days of monensin challenge for group C cows was 2.7 d, with a range of 2 to 4 d. No cows were euthanized due to meeting the cow removal criteria.
Dry matter feed intake (DMI)
Mean daily DMI for all cows by treatment group (including cows that were returned to a non-medicated diet after reaching anorexia criteria) are presented in Table I. Table II (challenge) illustrates the impact of treatment on both DMI and milk production, excluding cows that were removed from exposure. Table III (recovery) demonstrates the production and intake data by days for the cows removed from monensin treatment.
Table I.
Dry matter intake (DMI) and milk production among lactating dairy cows evaluating the impact of receiving monensin in excess of daily-recommended levels
| Trial day
|
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Group | pre tx | 0 | 1 | 2 | 3b | 4c | 10 | 15 | 20d | |
| Daily dry matter intakea | ||||||||||
| 72 ppm | mean (kg) | 22.8 | 20.4 | 20.3 | 17.6 | 18.8 | 19.1 | 20.0 | 21.3 | 20.8 |
| n = 6 | s (kg) | 3.1 | 2.6 | 3.1 | 4.7 | 3.2 | 3.3 | 3.1 | 3.4 | 2.7 |
| % pre tx | 89.3 | 89.2 | 77.0 | 82.4 | 83.8 | 87.7 | 93.4 | 91.3 | ||
| 144 ppm | mean (kg) | 21.7 | 18.4 | 15.2 | 13.4 | 15.0 | 16.1 | 21.0 | 21.6 | 21.8 |
| n = 66 | s (kg) | 3.1 | 2.9 | 3.5 | 4.5 | 3.1 | 3.3 | 4.1 | 3.4 | 2.7 |
| % pre tx | 85.0 | 70.2 | 61.7 | 69.2 | 74.4 | 96.6 | 99.5 | 100.3 | ||
| 240 ppm | mean (kg) | 22.7 | 17.8 | 10.4 | 11.8 | 15.9 | 19.3 | 22.2 | 22.0 | 22.6 |
| n = 66 | s (kg) | 2.4 | 2.0 | 2.2 | 2.1 | 5.1 | 3.3 | 3.9 | 4.0 | 2.4 |
| % pre tx | 78.5 | 45.9 | 51.8 | 70.0 | 85.1 | 97.9 | 97.0 | 99.5 | ||
| Daily milk productiona | ||||||||||
| 72 ppm | mean (kg) | 38.0 | 37.5 | 37.2 | 36.8 | 35.1 | 35.5 | 36.1 | 34.9 | 36.2 |
| n = 66 | s (kg) | 2.9 | 5.3 | 2.6 | 2.0 | 3.0 | 1.1 | 1.9 | 1.6 | 3.2 |
| % pre tx | 98.6 | 97.9 | 96.9 | 92.3 | 93.5 | 94.9 | 91.7 | 95.2 | ||
| 144 ppm | mean (kg) | 39.1 | 38.3 | 37.2 | 33.1 | 31.4 | 32.5 | 38.1 | 37.4 | 37.2 |
| n = 66 | s (kg) | 3.4 | 4.9 | 3.2 | 3.5 | 3.7 | 3.0 | 3.4 | 4.1 | 4.2 |
| % pre tx | 98.0 | 95.1 | 84.7 | 80.2 | 83.1 | 97.4 | 95.5 | 95.1 | ||
| 240 ppm | mean (kg) | 39.6 | 41.0 | 35.2 | 28.0 | 29.6 | 33.3 | 38.9 | 37.6 | 39.8 |
| n = 66 | s (kg) | 3.7 | 4.1 | 2.9 | 3.4 | 4.1 | 5.7 | 5.0 | 3.1 | 6.5 |
| % pre tx | 103.5 | 88.8 | 70.7 | 74.7 | 84.0 | 98.3 | 95.0 | 100.5 | ||
pre tx — Pretreatment period; % pre tx — Percentage of pretreatment value; s — Standard deviation
Includes all animals, those receiving monensin and those returned to a non-medicated diet after reaching anorexia criteria. No significant differences for dry matter intake or milk production existed pretreatment
All cows given 240 ppm monensin were removed from treatment by day 3
All cows given 144 ppm monensin were removed from treatment by day 4
4 cows given 72 ppm monensin remained on treatment until day 20
Table II.
Challenge — Dry matter intake (DMI) and milk production among lactating dairy cows evaluating the impact of receiving monensin in excess of daily-recommended levels during challenge (while receiving monensin only)
| Trial day
|
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Group | pre tx | 0 | 1 | 2 | 3 | 4 | 10 | 15 | 20 | |
| Daily dry matter intakea | ||||||||||
| 72 ppm | mean (kg) | 22.8 | 20.4 | 20.3 | 17.6 | 18.8 | 19.1 | 19.7 | 20.6 | 20.9 |
| n | 6 | 6 | 6 | 6 | 6 | 6 | 5 | 4 | 4 | |
| s (kg) | 3.1 | 2.6 | 3.1 | 4.7 | 3.2 | 3.3 | 3.1 | 2.0 | 2.3 | |
| % pre tx | 100 | 89.5 | 89.4 | 77.2 | 82.6 | 84.0 | 84.2 | 84.9 | 86.4 | |
| 144 ppm | mean (kg) | 21.7 | 18.4 | 15.2 | 13.4 | 14.8 | 14.1 | — | — | — |
| n | 6 | 6 | 6 | 6 | 5 | 2 | ||||
| s (kg) | 3.2 | 2.8 | 1.3 | 2.9 | 1.1 | 1.3 | — | — | — | |
| % pre tx | 100 | 84.8 | 70.1 | 61.6 | 66.0 | 70.8 | — | — | — | |
| 240 ppm | mean (kg) | 22.7 | 17.8 | 10.4 | 11.5 | 8.8 | — | — | — | — |
| n | 6 | 6 | 6 | 3 | 1 | |||||
| s (kg) | 2.4 | 2.0 | 2.2 | 0.13 | — | — | — | — | — | |
| % pre tx | 100 | 78.7 | 46.0 | 53.0 | 42.8 | — | — | — | — | |
| Daily milk productiona | ||||||||||
| 72 ppm | mean (kg) | 38.0 | 37.5 | 37.2 | 36.8 | 35.1 | 35.5 | 36.7 | 30.9 | 35.6 |
| s (kg) | 2.9 | 5.3 | 2.6 | 2.0 | 3.0 | 1.1 | 1.3 | 6.7 | 2.2 | |
| % pre tx | 100 | 98.5 | 97.8 | 96.8 | 92.2 | 93.4 | 94.1 | 80.0 | 92.1 | |
| 144 ppm | mean (kg) | 39.1 | 38.3 | 37.2 | 33.1 | 32.0 | 33.8 | — | — | — |
| s (kg) | 4.0 | 4.5 | 3.9 | 3.8 | 3.6 | 1.3 | — | — | — | |
| % pre tx | 100 | 98.1 | 95.2 | 84.8 | 80.4 | 84.1 | — | — | — | |
| 240 ppm | mean (kg) | 39.6 | 41.0 | 35.2 | 28.3 | 29.6 | — | — | — | — |
| s (kg) | 3.7 | 4.1 | 2.9 | 3.0 | — | — | — | — | — | |
| % pre tx | 100 | 103 | 88.7 | 71.6 | 81.5 | — | — | — | — | |
pre tx — Pretreatment period; % pre tx — Percentage of pretreatment value; s — Standard deviation
Cows included until anorexia criteria were met and the cows were removed from the study. Numbers (n) per treatment group the same for milk production data as indicated for daily DMI data above
Table III.
Recovery — Dry matter intake (DMI) and milk production among lactating dairy cows that received an excess of daily-recommended levels of monensin and then had monensin removed from the diet
| Days from removal of monensin
|
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Group | Pre tx | 1 | 2 | 3 | 4 | 5 | 7 | 10 | 15 | |
| Daily dry matter intakea | ||||||||||
| 72 ppm | mean (kg) | 19.8 | 15.2 | 16.8 | 18.2 | 19.6 | 17.9 | 18.7 | — | — |
| n = 62 | % pre tx | 100 | 76.0 | 84.8 | 91.9 | 99.0 | 90.3 | 94.0 | — | — |
| 144 ppm | mean (kg) | 21.7 | 15.3 | 16.5 | 18.1 | 19.5 | 20.8 | 22.3 | 21.4 | 23.0 |
| n = 66 | % pre tx | 100 | 70.4 | 75.8 | 83.3 | 89.5 | 95.4 | 102.7 | 98.6 | 105.6 |
| 240 ppm | mean (kg) | 22.7 | 13.3 | 12.8 | 18.7 | 20.3 | 20.3 | 22.4 | 22.0 | 22.8 |
| n = 66 | % pre tx | 100 | 58.9 | 56.6 | 82.5 | 89.6 | 89.5 | 98.7 | 96.9 | 100.7 |
| Daily milk productiona | ||||||||||
| 72 ppm | mean (kg) | 36.8 | 33.8 | 34.3 | 34.2 | 35.7 | 35.3 | 38.6 | — | — |
| n = 62 | % pre tx | 100 | 91.8 | 93.2 | 92.8 | 96.9 | 95.8 | 104.9 | — | — |
| 144 ppm | mean (kg) | 39.1 | 35.1 | 32.1 | 33.4 | 35.5 | 37.4 | 38.2 | 37.9 | 37.9 |
| n = 66 | % pre tx | 100 | 89.8 | 82.1 | 85.4 | 90.9 | 95.6 | 97.8 | 97.0 | 97.1 |
| 240 ppm | mean (kg) | 36.9 | 36.8 | 27.3 | 30.4 | 35.3 | 36.9 | 39.6 | 38.6 | 39.4 |
| n = 66 | % pre tx | 100 | 92.7 | 68.8 | 76.6 | 88.9 | 93 | 100 | 97.5 | 99.3 |
pre tx — Pretreatment period; % pre tx — Percentage of pretreatment value
Cows included until anorexia criteria were met and the cows were removed from the study. Numbers (n) per treatment group the same for milk production data as indicated for daily DMI data above
Cows in group A consumed approximately 80% to 90% of their prechallenge DMI for the entire challenge period. Cows in group B showed a decline in DMI of between 30% and 40% on the 2nd and 3rd d of the challenge period. Cows in group C demonstrated a rapid decrease in feed intake to less than 50% by the 2nd d of the challenge. All cows removed from monensin challenge returned to between 95% and 100% prechallenge feed intakes approximately 7 d after returning to a non-medicated ration. Average daily DMI by treatment group for cows receiving monensin (with cows meeting anorexia criteria removed) are presented in Figure 1.
Figure 1.
Daily dry matter intake (DMI) among lactating cows receiving monensin in excess of daily-recommended levels. From day −14 to day −1, cows received monensin at 24 ppm in the feed. Levels were increased 3 × (72 ppm), 6 × (144 ppm), and 10 × (240 ppm). Numbers in italics within the figure correspond to the number of cows remaining on monensin. Cows not receiving monensin because they met the anorexia criteria are not included.
Daily milk production and milk residues
All 124 milk samples collected were below the limit of monensin quantification of 0.005 mg/mL. Mean daily milk production for all cows by treatment group (including cows returned to a nonmedicated diet after reaching anorexia criteria) are presented in Table I. None of the 3 treatments had any impact on milk production on the 1st d of the challenge period. Among the group A cows receiving monensin, mean milk production decreased from the prechallenge period by between 5% to 15% over the 21 d study period. Mean milk production among group B cows dropped by 20% by the 4th d of challenge. Mean milk production among group C cows dropped by 30% by the 3rd d of the challenge period. Average daily milk production by treatment group for cows receiving monensin is presented in Figure 2.
Figure 2.
Daily average milk production (± standard error of means) among cows receiving monensin in excess of daily-recommended levels. From day −14 to day −1, cows received monensin at 24 ppm in the feed. Levels were increased 3 × (72 ppm), 6 × (144 ppm), and 10 × (240 ppm). Numbers in italics within the figure correspond to the number of cows remaining on monensin. Cows not receiving monensin because they met the anorexia criteria are not included.
Discussion
In lactating Holstein cows receiving up to 4865 mg monensin per day in a TMR ration (in excess of 10 times the 24 ppm dose), there were no detectable monensin residues (that is, < 0.005 μg/mL) in any of the milk samples collected.
Results of the present study support the findings of others that have evaluated monensin milk residues in lactating cattle (4,5). Among these studies previously conducted on residues, monensin was not found in milk (4,5). In all of these studies the assay for determining monensin residue in milk was based on HPLC with a minimum detection limit of 5 ppb (9). The highest level of monensin administered in these studies was 1125 mg/head per day and unpublished data exists for up to 1274.4 mg/head per day (6). Results of the present study suggest a very high margin of safety as cows were receiving up to 4865 mg monensin per day (over 10 times the recommended daily dose). No studies currently exist where humans were intentionally exposed to monensin. However, Health Canada has recently set the administrative maximum residue limit for monensin in milk at 10 ppb, which is twice the limit of quantification for the assay used in this study. Not unexpectedly, cows receiving monensin in excess of the daily recommended dose experienced reduced feed intake and milk production. In this study, lactating cows preadapted to monensin in the feed at 24 ppm and then suddenly switched to a dose of 72 ppm, exhibited up to a 20% reduction in DMI and a drop in milk production of between 5% and 15% from the prechallenge period. Cows fed monensin in TMR at both 144 ppm and 240 ppm exhibited rapid decreases in feed intake of up to 50% by the 2nd d of feeding. Once cows were switched to a non-medicated ration, feed intakes recovered to between 95% and 100% of the prechallenge levels within 7 d. At both 144 ppm and 240 ppm, milk production dropped by up to 20% to 30%, respectively, within 4 d, and then gradually recovered to between 95% and 100% of the prechallenge period after the cows were switched to an unmedicated diet. Reductions in DMI and milk production with monensin intoxication have been reported previously (4,10).
It is important to note that cows in this trial were previously adapted to receiving monensin before the challenge of higher toxic doses were administered. Sudden exposure to high doses without previous adaptation could have more serious and sudden impacts on feed intake and milk production. However, no difference would be expected in the levels of residues as compared to this study because the impacts of lack of adaptation would be directly mediated through rumen bacteria and not through changes in liver metabolism of monensin.
In conclusion, results of this study confirm the safety of food products derived from lactating dairy cattle receiving monensin at recommended levels for human consumption.
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