Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling.

Some synthetic chemicals are suspected to be responsible for adverse effects on endocrine function. Sex hormones administered to farm animals are of particular interest because of their regulatory role in developmental processes. To predict concentrations in humans of the synthetic growth promoter melengestrol acetate (17α-acetoxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione), a forward dosimetry approach was carried out using data from no-observed-adverse-effect-level doses orally administered to mice or rats and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated 2-hydroxylation of melengestrol acetate, but rodent livers produced additional unidentified hydroxymetabolites. Adjusted animal biomonitoring equivalents for melengestrol acetate from mouse and rat studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. Melengestrol acetate elimination in humans was estimated to be slow compared with elimination in rodents. The disposition of melengestrol acetate in humans was evaluated using chimeric TK-NOG mice with humanized liver. The results suggest the usefulness of simplified PBPK modeling combined with in vitro and in vivo experiments and literature resources as well as a future interest in estimating by a full PBPK modeling using another bottom up system. This model may also be useful for risk evaluation and for simulating plasma concentrations resulting from exposure to low doses of melengestrol acetate and related compounds.

The fate of trenbolone acetate and melengestrol acetate after application as growth promoters in cattle: environmental studies.

The steroids trenbolone acetate (TbA) and melengestrol acetate (MGA) are licensed as growth promoters for farm animals in several meat-exporting countries. Although many studies have explored their safety for both animals and consumers, little is known about their fate after excretion by the animal. Our study aimed to determine the residues and degradation of trenbolone and MGA in solid dung, liquid manure, and soil. In animal experiments lasting 8 weeks, cattle were treated with TbA and MGA. Solid dung and, in case of trenbolone, liquid manure were collected and spread on maize fields after 4.5 and 5.5 months of storage, respectively. Determination of the hormone residues in all samples included extraction, clean-up (solid-phase extraction), separation of metabolites and interfering substances by HPLC (RP-18), and quantification by sensitive enzyme immunoassay. Procedures were validated by mass spectrometry (MS) methods. During storage of liquid manure the level of trenbolone decreased from 1,700 to 1,100 pg/g (17alpha-isomer), corresponding to a half-life of 267 days. Before storage, the concentrations in the dung hill ranged from 5 to 75 ng/g TbOH and from 0.3 to 8 ng/g MGA. After storage, levels up to 10 ng/g trenbolone, and 6 ng/g MGA were detected. In the soil samples trenbolone was traceable up to 8 weeks after fertilization, and MGA was detected even until the end of the cultivation period. The results show that these substances should be investigated further concerning their potential endocrine-disrupting activity in agricultural ecosystems.

Detection of melengestrol acetate residues in plasma and edible tissues of heifers.

The aim of this study was to gain knowledge of residue formation after the use of melengestrol acetate (MGA) as a growth-promoting agent. Two Holstein-Friesian heifers each received a daily dose through the feed of 0, 0.5 mg (2 heifers with and without withdrawal each), 1.5 mg or 5.0 mg MGA for 8 weeks. MGA residues in plasma were screened by enzyme immuno-assay (EIA). Concentrations in kidney, liver, and muscle were quantified by liquid-chromatography-mass spectrometry (LC-MS), and in fat by gas chromatography-mass spectrometry (GC-MS). MGA levels in plasma were 40, 128, and 280 ng/L, respectively. Residues accumulated in muscle and kidney (5-fold), liver (20-to-40-fold), and fat (200-fold). After administration of 1.5 mg per day the mean MGA concentration in fat was 29 micrograms/kg and thus violated USA regulations which specify a limit of 25 ppb. Therefore the labelled use of MGA (0.5 mg per day) has to be officially controlled.

Effect of melengestrol acetate on development of 3-methylindole-induced pulmonary edema and emphysema in sheep.

The involvement of melengestrol acetate (MGA) in susceptibility to developing pulmonary edema and emphysema following oral administration of 3-methylindole (3MI) was investigated using 10 Suffolk ewes receiving 0 or 0.15 mg of MGA daily (n = 5). Blood, urine and ruminal fluid were collected immediately prior to 3MI dosing (0.2 g/kg BW) and 1, 2, 3, 4, 5, 6, 12 and 24 h (blood); 3, 6, 9, 12 and 15 h (urine) and 1, 2, 3 and 12 h (ruminal fluid) afterward. Ewes receiving MGA experienced earlier (P < 0.05) onset of respiratory distress than the control ewes (2.5 vs 4 h), and upon euthanasia at 96 h, their lung weight relative to body weight tended (P < 0.10) to be lower. Ruminal 3MI concentrations did not differ between treatments (P > 0.05). Ewes receiving MGA had higher (P < 0.05) concentrations of 3MI metabolites in plasma prior to dosing than did control ewes, and these values tended to remain higher throughout the sampling period. Immunoreactivity assays indicated more pneumotoxin present in the lungs of MGA-treated ewes than controls. Lung damage was apparently more acute and accelerated in the MGA-treated ewes than in the controls. Urinary 3MI mercapturate concentrations differed (control > MGA-treated, P < 0.05) at 9, 12, and 15 h, but this difference was not apparent when urinary production (as estimated by creatinine concentration) was considered. The implications of these findings for MGA-treated feedlot heifers are currently under investigation.