Optimizing maintenance therapy in responders to abrocitinib induction: A post hoc analysis of JADE REGIMEN.

BACKGROUND: Treatment optimization may require dosing flexibility. The Phase 3 JADE REGIMEN trial (NCT03627767) evaluated maintenance of abrocitinib 200 mg-induced response in patients with moderate-to-severe atopic dermatitis (AD) randomly assigned to subsequent maintenance with continuous-dose abrocitinib (200 mg), reduced-dose abrocitinib (100 mg) or placebo. Maintenance with continuous-dose abrocitinib was associated with a stronger prevention of disease flares, but also with a higher occurrence of adverse events, compared with the reduced dose. OBJECTIVE: This post hoc analysis of JADE REGIMEN aimed to identify predictors of not flaring during the maintenance period and to generate tools that can be used to assess probability of not flaring. METHODS: Data were analysed from patients who responded to abrocitinib 200 mg induction therapy (12 weeks) and were randomly assigned to receive abrocitinib (200 mg or 100 mg) or placebo in the 40-week maintenance period. Demographic and baseline disease characteristics and level of response to induction were evaluated for association with not flaring using logistic regression. Parameters with a significant (p < 0.15) interaction with the treatment arm were fitted into a multivariable regression model, which was used to assess probability of not flaring. RESULTS: Lower percentage body surface area affected at baseline (p = 0.09), absence of prior exposure to systemic agents (p = 0.02) and greater percentage change in EASI from baseline to randomization (p < 0.001) were identified as predictors of not flaring with abrocitinib. In both abrocitinib arms, percentage change in EASI from baseline to end of induction (Week 12) was the major contributor to the probability of not flaring in the maintenance period. CONCLUSIONS: Maintenance of response using reduced-dose abrocitinib 100 mg may be feasible for patients with lower baseline disease severity and strong response to abrocitinib 200 mg induction treatment.

Reliability of sonomyography for pectoralis major thickness measurement.

OBJECTIVE: Muscle thickness is a widely used parameter for quantifying muscle function in ultrasound imaging. However, current measurement techniques generally rely on manual digitization, which is subjective, time consuming, and prone to error. The primary purposes of this study were to develop an automated muscle boundary tracking algorithm to overcome these limitations and to report its intraexaminer reliability on pectoralis major muscle. METHODS: Real-time B-mode ultrasound images of the pectoralis major muscles were acquired by an integrated data acquisition system. A transducer placement protocol was developed to facilitate better repositioning of an ultrasound transducer. Intraexaminer reliability of the tracking algorithm for static measurements was studied using intraclass correlation coefficient based on the thickness data from 11 healthy subjects recruited from a chiropractic college measured at 3 independent sessions. Standard error of measurement and minimal detectable change were calculated. Feasibility of using the tracking algorithm for dynamic measurements was also evaluated. RESULTS: All calculated intraclass correlation coefficients were larger than 0.96, indicating excellent reliability of the sonomyographic measurements. Minimal detectable changes were 9.7%, 6.7%, and 6.8% of the muscle thickness at the lateral, central, and medial aspects, respectively. For a 400-frame image stack with 3 pairs of 40 x 40 pixels tracking windows, the tracking took about 80 seconds to complete. CONCLUSIONS: The tracking algorithm offers precise and reliable measurements of muscle thickness changes in clinical settings with potential to quantify the effects of a wide variety of chiropractic techniques on muscle function.

A computer aided method for closed reduction of diaphyseal tibial fracture using projection images: A feasibility study.

A computer aided method for closed tibial shaft fracture reduction based on measurements of 12 projection parameters (6 angulations and 6 translations) from an anteroposterior radiograph, a lateral radiograph, and a transverse projection photograph is examined. The development, validation and reliability of the computer aided method are presented. A custom-made unilateral external fixation device consisting of 7 calibrated one-degree-of-freedom joints was employed to execute the reduction. Five tibial fracture phantoms with initial deformities that covered a wide range of misalignments were tested. The mean (standard deviation) resultant rotational and translational errors after the reduction were 3.32° (0.96°) and 1.65 (0.86) mm, respectively, which indicates good reduction accuracy. Three independent raters made the measurements of the projection parameters to test inter-rater reliability. The intra-class correlation coefficients were found to range between 0.935 and 1, indicating good reliability. Since ideal patient positioning for AP, lateral and transverse image acquisition is not easily attainable, the effect of patient positioning errors on the measurement of projection parameters was explored using a tibial phantom. The preliminary results revealed that 10° deviations in positioning do not greatly affect the measurement of AP and lateral angulation parameters (<1.7°). However, a 10° positioning error about the long bone axis may result in a change of as much as 10.7° in the measurements of transverse projection angulation parameters. In addition, a 10° positioning error about an arbitrary anatomical axis may result in translational projection parameter changes of up to 6.8 mm. For these reasons, a previously validated method that allows for accurate positioning of the tibia about its long axis and a two-step reduction strategy to achieve the best possible deformity reduction are proposed. Procedures to facilitate reliable measurement of tibial torsion are also discussed. It appears that the projection-based reduction method exposes the patient to less radiation and allows for simple, quick and accurate reductions, making it an attractive choice for acute clinical applications.

Effects of gestational age on prostaglandin EP receptor expression and functional involvement during in vitro contraction of the guinea pig uterus.

Prostaglandin E(2) (PGE(2)) exerts diverse biological effects through four G-protein-coupled cell surface receptor subtypes, EP1-4. This study's objective was to characterize EP1-4 receptor mRNA expression within pregnant guinea pig myometrium during early implantation stage (gestation day [GD] 6) and late stage gestation (GD 50) and evaluate in vitro contractile activity of receptor subtype selective agonists. Using RT-PCR, qualitative gene expression patterns of EP2, EP3, and EP4 mRNA were detected in the myometrium and remained unchanged between the gestational ages. EP1 mRNA remained undetected in pregnant tissue. In vitro contractile activity was evaluated in GD 6 and GD 50 myometrium using vehicle and EP agonists PGE(2), 17-phenyl trinor PGE(2), sulprostone, misoprostol, and CP-533,536. All spasmogens in pregnant myometrium were EP1/EP3 selective agonists, though likely acting via EP3 receptors in this test model. CP-533,536--a highly selective EP2 receptor agonist--and the vehicle failed to induce myometrial contraction at both gestational ages.

Is maximum isometric muscle stress the same among prime elbow flexors?

BACKGROUND: Previous musculoskeletal modeling studies have adopted the assumption of the same maximum isometric muscle stress among the prime elbow flexors. This study aimed at estimating the maximum isometric muscle stress based on subject-specific modeling parameters measured in vivo and validating that assumption. METHODS: Subject-specific musculoskeletal models of the upper limbs of five normal subjects were developed, which incorporated anthropometrically scaled graphics-based geometrical models and Hill-type musculotendon models of the prime elbow flexors. B-mode ultrasound technique was employed to measure the muscle optimal length and pennation angle of each prime elbow flexor, and these architectural parameters were inputted into the model to reduce the number of unknown parameters to be optimized. To allow changes of individual maximum isometric muscle force of the prime elbow flexors, optimizations were conducted by minimizing the root mean square difference between the predicted and measured isometric torque-angle curves. Maximum isometric muscle stress of each prime elbow flexor was estimated by dividing the maximum isometric muscle force with the corresponding physiological cross-sectional area. FINDINGS: Our findings showed that maximum isometric muscle stress among the prime elbow flexors was not significantly different from each other. Thus it appears that it is reasonable to assume the same value for maximum isometric muscle stress for all prime elbow flexors in musculoskeletal modeling studies. INTERPRETATION: Latest medical imaging techniques such as ultrasound for the estimation of musculotendon parameters would provide an alterative method to obtain the muscle architecture parameters noninvasively. The subject-specific musculotendon parameters estimated in this study could be used for developing the neuromusculoskeletal model to predict muscle force and evaluate muscle functions.

A knowledge-based computer-aided system for closed diaphyseal fracture reduction.

BACKGROUND: We recently developed an algorithm to perform closed fracture reduction using unilateral external fixator. Although its validity has been verified experimentally, the whole reduction process was not evaluated owing to the lack of a device that could facilitate its implementation in clinical practice. The objective of this study is to develop a prototype of such a system, and quantify its reduction accuracy. METHODS: The system consists of a custom-made unilateral external device and a self-contained software package. The device features 7 one degree of freedom joints, each allows for continuous adjustments and is equipped with measurement components to facilitate accurate positioning. A CT-based method was developed, which facilitates virtual reduction and calculates the adjustment requirements that reduce a fracture deformity. The device was adjusted off-the-site and reattached back in place to guide the reduction of the fracture fragments. Reduction accuracy was evaluated using eight phantoms of different types, sides and fracture patterns by calculating the rotation about a screw axis and the displacement between the origins of the distal and proximal local coordinate systems after the reduction. FINDINGS: The mean (SD) of the translational and rotational reduction errors were 1.73 (0.97)mm and 2.57 degrees (1.36 degrees), respectively, which demonstrated the accuracy and reliability of the system. INTERPRETATION: The system allows surgeons to perform fracture reduction in an objective, efficient, and accurate manner yet minimize the radiation exposure and lessens the extent of tissue disruption around the fracture site during the reduction process.

A neuromusculoskeletal model to simulate the constant angular velocity elbow extension test of spasticity.

We developed a neuromusculoskeletal model to simulate the stretch reflex torque induced during a constant angular velocity elbow extension by tuning a set of physiologically-based parameters. Our model extended past modeling efforts in the investigation of elbow spasticity by incorporating explicit musculotendon, muscle spindle, and motoneuron pool models in each prime elbow flexor. We analyzed the effects of changes in motoneuron pool and muscle spindle properties as well as muscle mechanical properties on the biomechanical behavior of the elbow joint observed during a constant angular velocity elbow extension. Results indicated that both motoneuron pool thresholds and gains could be substantially different among muscles. In addition, sensitivity analysis revealed that spindle static gain and motoneuron pool threshold were the most sensitive parameters that could affect the stretch reflex responses of the elbow flexors during a constant angular velocity elbow extension, followed by motoneuron pool gain, and spindle dynamic gain. It is hoped that the model will contribute to the understanding of the underlying mechanisms of spasticity after validation by more elaborate experiments, and will facilitate the future development of more specific treatment of spasticity.

Effects of feed restriction on fertility in female rats.

BACKGROUND: Feed restriction with its resultant body weight loss impacts the rodent estrous cycle; however, the manifestation of these changes in a regulatory study design has not been documented. This study reports the effects of feed restriction in the context of an FDA regulatory submission. METHODS: Adult female rats (n = 20/group; weighing approximately 200 g each) were provided rodent chow ad lib (control) or at 20, 15, 10, or 7.5 g/rat/day (g/day) during a 2-week pre-mating phase, throughout the mating phase, and up to gestation day (GD) 7. On GD 8, all animals were provided ad lib feed until necropsy on GD 14. Estrous cyclicity, mating, and fertility parameters were evaluated. RESULTS: Ad lib rats consumed approximately 20 and 28 g/day during the pre-mating and gestation phases, respectively. All measured fertility parameters in the 20 g/day group were similar to control values. In the 15 g/day group, body weight was reduced by 16% at 2 weeks, prolonged diestrus occurred, and fertility was compromised due to reductions in corpora lutea. Within 2 weeks, mean body weight in groups receiving < or = 10 g/day was reduced by > or = 29% compared to ad lib values, and overt changes in estrous cyclicity, mating, and fertility occurred. The 7.5 g/day group was not sustainable beyond the pre-mating phase. CONCLUSIONS: For this study type, feed intake at < or = 50% ad lib values (< or = 10 g/day) was inadequate due to the magnitude and rapidity of body weight effects. Estrous parameters appeared slightly more sensitive than functional measures, as body weight changes of approximately 16% appeared near the threshold of changing routinely calculated estrous cycle parameters and were later associated with reduced fertility. In general, body weight differences of 10-15% by themselves were not adverse to normal reproduction (20 g/day).

Feasibility of using EMG driven neuromusculoskeletal model for prediction of dynamic movement of the elbow.

Neuromusculoskeletal (NMS) modeling is a valuable tool in orthopaedic biomechanics and motor control research. To evaluate the feasibility of using electromyographic (EMG) signals with NMS modeling to estimate individual muscle force during dynamic movement, an EMG driven NMS model of the elbow was developed. The model incorporates dynamical equation of motion of the forearm, musculoskeletal geometry and musculotendon modeling of four prime elbow flexors and three prime elbow extensors. It was first calibrated to two normal subjects by determining the subject-specific musculotendon parameters using computational optimization to minimize the root mean square difference between the predicted and measured maximum isometric flexion and extension torque at nine elbow positions (0-120 degrees of flexion with an increment of 15 degrees ). Once calibrated, the model was used to predict the elbow joint trajectories for three flexion/extension tasks by processing the EMG signals picked up by both surface and fine electrodes using two different EMG-to-activation processing schemes reported in the literature without involving any trajectory fitting procedures. It appeared that both schemes interpreted the EMG somewhat consistently but their prediction accuracy varied among testing protocols. In general, the model succeeded in predicting the elbow flexion trajectory in the moderate loading condition but over-drove the flexion trajectory under unloaded condition. The predicted trajectories of the elbow extension were noted to be continuous but the general shape did not fit very well with the measured one. Estimation of muscle activation based on EMG was believed to be the major source of uncertainty within the EMG driven model. It was especially so apparently when fine wire EMG signal is involved primarily. In spite of such limitation, we demonstrated the potential of using EMG driven neuromusculoskeletal modeling for non-invasive prediction of individual muscle forces during dynamic movement under certain conditions.

Biomechanical considerations of fracture treatment and bone quality maintenance in elderly patients and patients with osteoporosis.

Osteoporosis is a major public health problem that is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures of the hip, spine, and wrist. Poor bone quality in patients with osteoporosis presents the surgeon with difficult treatment decisions. Bone fracture repair has more pathways with combinations of bone formation mechanisms, which depend on the type of fracture fixation to be applied to achieve the desirable immobilization. There only may be one remodeling principle and in less than ideal conditions, mechanical and biophysical stimuli may provide effective augmentation of fracture healing in elderly patients. A different stimulus may limit its association to a specific healing mechanism. However, no matter which fixation method is used, an accurate reduction is a requisite for bone healing. Failure to realign the fracture site would result in delayed union, malunion, or nonunion. Therefore, a basic understanding of the biomechanics of osteoporotic bone and its treatment is necessary for clinicians to establish appropriate clinical treatment principles to minimize complications and enhance the patient's quality of life. We describe the biomechanical considerations of osteoporosis and fracture treatment from various aspects. First, bone structure and strength characterization are discussed using a hierarchical approach, followed by an innovative knowledge-based approach for fracture reduction planning and execution, which particularly is beneficial to osteoporotic fracture. Finally, a brief review of the results of several experimental animal models under different fracture types, gap morphologic features, rigidity of fixation devices, subsequent loading conditions, and biophysical stimulation is given to elucidate adverse mechanical conditions associated with different bone immobilization techniques that can compromise normal bone fracture healing significantly.

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats.

BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM). With high affinity to the alpha and beta human estrogen receptors and greater potency than other SERMs, lasofoxifene is potentially a superior treatment for postmenopausal osteoporosis. In light of the known effects of estrogen-modulating compounds on female reproductive indices, two studies were conducted to evaluate the effects of lasofoxifene on female rat cyclicity, reproduction, and parturition. METHODS: One study evaluated effects of lasofoxifene on estrous cyclicity, and the second study assessed effects on implantation and parturition. In the cyclicity study, lasofoxifene was administered to female rats at doses of 0.1, 0.3, and 1.0 mg/kg/day for 14 consecutive days. After treatment, there was a 3-week reversibility phase followed by a mating phase. In the implantation study, lasofoxifene was administered to pregnant female rats at doses of 0.01, 0.03, and 0.1 mg/kg/day for 7 consecutive days (gestation day [GD] 0-6). Some animals were euthanized on GD 21, and the remainder of the group was allowed to deliver the F1 generation. Several developmental indices were evaluated in the F1 pups through post-natal day (PND) 21. RESULTS: In the cyclicity study, all lasofoxifene-treated females were anestrous by Study Day 7 (1.0 mg/kg) or 9 (0.3 and 0.1 mg/kg). The reversibility phase resulted in restoration of normal estrous cycles by the end of 1 (0.1 mg/kg) or 2 weeks (0.3 and 1.0 mg/kg). During the mating phase, no adverse effects occurred in pregnancy success or reproductive parameters. In the implantation study, all doses of lasofoxifene increased pre- and post-implantation losses, increased gestation length, and reduced litter size. None of the developmental parameters measured on the F1 generation was adversely affected. CONCLUSION: Lasofoxifene reversibly altered the estrous cycle and inhibited implantation, consistent with what would be expected from a member of the SERM class.

In vivo determination of subject-specific musculotendon parameters: applications to the prime elbow flexors in normal and hemiparetic subjects.

OBJECTIVE: This study aimed at estimating the musculotendon parameters of the prime elbow flexors in vivo for both normal and hemiparetic subjects. DESIGN: A neuromusculoskeletal model of the elbow joint was developed incorporating detailed musculotendon modeling and geometrical modeling. BACKGROUND: Neuromusculoskeletal modeling is a valuable tool in orthopedic biomechanics and motor control research. However, its reliability depends on reasonable estimation of the musculotendon parameters. Parameter estimation is one of the most challenging aspects of neuromusculoskeletal modeling. METHODS: Five normal and five hemiparetic subjects performed maximum isometric voluntary flexion at nine elbow positions (0 degrees -120 degrees of flexion with an increment of 15 degrees ). Maximum flexion torques were measured at each position. Computational optimization was used to search for the musculotendon parameters of four prime elbow flexors by minimizing the root mean square difference between the predicted and the experimentally measured torque-angle curves. RESULTS: The normal group seemed to have larger maximum muscle stress values as compared to the hemiparetic group. Although the functional ranges of each selected muscle were different, they were all located at the ascending limb of the force-length relationship. The muscle optimal lengths and tendon slack lengths found in this study were comparable to other cadaver studies reported in the literature. CONCLUSION: Subject-specific musculotendon parameters could be properly estimated in vivo. RELEVANCE: Estimation of subject-specific musculotendon parameters for both normal and hemiparetic subjects would help clinicians better understand some of the effects of this pathological condition on the musculoskeletal system.

Lack of embryotoxicity of fumonisin B1 in New Zealand white rabbits.

Fumonisin B1 (FB1) is one of a number of mycotoxins produced by fungi, especially Fusarium sp. As a contaminant of many maize-derived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3-19 with purified FB1 at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive implantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB1 did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB1.

Effects of 2-methoxyethanol on mouse neurulation.

The potent developmental toxicant, 2-methoxyethanol (2-ME), elicits exencephaly in near-term mouse fetuses following a single maternal treatment early on gestation day (gd) 8. Deleterious morphological consequences to the neurulating embryo shortly after exposure have not been reported. The present study was designed to fill this gap and to investigate the impact of 2-ME treatment on cell death patterns in the embryonic neural folds. Dams were injected subcutaneously with saline, 250 or 325 mg 2-ME/kg 2 hr prior to the beginning of gd 8. The effect of 2-ME on gross and microscopic neural development was examined in conceptuses on gd 9, 6 hr (9:6), 10:6, and 18:0. Compared to saline, 2-ME treatment increased the percentage of embryos with open neural tubes (ONTs) at all gestation days. Although few statistically significant differences (P < 0.05) existed among the ONT rates on the 3 observation days, an interesting biological response occurred. Both high and low 2-ME doses appeared to elicit the greatest incidence of neural tube patency on gd 9:6 (affecting approximately 27% of embryos). During the subsequent 24 hr, recovery occurred and many neural folds apparently closed. Consequently, the ONT incidences on gd 10:6 (approximately 11%) were quite similar to the gd 18 exencephaly rates elicited by both chemical treatments (approximately 15%). A dose response was not seen due to a substantial increase in resorption rates following the 325 mg/kg dose. Compared to the other treatment groups, the low 2-ME dose significantly inhibited embryonic growth as indicated by reduced crown-rump and head lengths and increased incidence of developmentally delayed brain maturation. To evaluate chemically induced changes in cell death, neurulating embryos were collected on gd 8:6 and either immersed in the vital dye, Nile blue sulfate (NBS), or processed for histopathology. In 2-ME-exposed embryos, excessive NBS uptake occurred in neural fold neuroepithelium at sites of nonclosure. Using histopathology, the extent of cell death in the cephalic neural folds was dependent on the 2-ME dose, and the neuroepithelium was more severely affected than the mesenchyme. These observations suggest 1) a trend toward repair and catch-up growth later in gestation which may ameliorate the overt early effects of 2-ME, and 2) an association between enhanced cell death and regions of the neural tube particularly vulnerable to nonclosure.

In vitro embryotoxicity of carbamazepine and carbamazepine-10, 11-epoxide.

Carbamazepine (Tegretol, CBZ) is an anticonvulsant drug that is very effective in the treatment of tonic-clonic seizures and is gaining acceptance as a treatment for various psychiatric disorders. The drug is embryotoxic in rodents and has been reported to produce neural tube defects in approximated 1% of prenatally exposed human offspring. It is metabolized by the cytochrome P-450 system to a stable, pharmacologically active epoxide intermediate, carbamazepine-10, 11-epoxide. It is currently unknown whether the parent compound, the epoxide intermediate or some other metabolite is the embryotoxic agent. The present study was designed to determine the embryotoxicity of CBZ and its epoxide intermediate (CBZ-E) in a rodent whole embryo culture system. Rat embryos were cultured beginning on day 9 of gestation (GD 9), and mouse embryos were cultured beginning in GD 8. All embryos were cultured for 48 hr in medium containing various concentrations of either CBZ or CBZ-E. Mice were more sensitive to the effects of CBZ than were rats. The parent compound was embryotoxic to mouse embryos at concentrations as low as 12 micrograms, but it was only embryotoxic at 60 micrograms/ml to rat embryos. CBZ-E was not embryotoxic to either species at concentrations as high as 48 micrograms/ml. These results suggest that the parent compound is the embryotoxic agent and that the epoxide intermediate plays no role in the drug's embryotoxic mechanism.

Development of a physiologically based pharmacokinetic model describing 2-methoxyacetic acid disposition in the pregnant mouse.

Using the potent developmental toxicant 2-methoxyethanol (2-ME) as a prototypical compound, a physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of its primary metabolite and proximate toxicant 2-methoxyacetic acid (2-MAA) in the pregnant CD-1 mouse. Data were collected during early, mid, and late organogenesis, specifically Gestation Days (GD) 8, 11, and 13 (GD 0 = plug-positive date). Pharmacokinetics and tissue partition coefficients for 2-MAA were determined in maternal plasma and conceptus on GD 8 and in maternal plasma, embryo, and extraembryonic/amniotic fluid (EAF) on GD 11 and 13. For simulation of GD 8 data, the conceptus was described as a single compartment, combining the yolk sac placenta, embryo, EAF, and decidua. For GD 11 and 13, the placenta, embryo, and EAF were explicitly described. Several hypotheses were tested for their ability to predict 2-MAA dosimetry. These hypotheses were encoded as alternative models having (a) blood flow-limited delivery of 2-MAA to model compartments, (b) pH trapping of ionized 2-MAA within compartments, (c) active transport of 2-MAA into compartments, and (d) reversible binding of 2-MAA within compartments. While the flow-limited description adequately predicted GD 8 dosimetry, the best simulations of the pharmacokinetic data collected on GD 11 and 13 were obtained with the active transport models. Since the mechanism by which 2-MAA accumulates into the embryo and EAF has not yet been elucidated, these mathematical descriptions are empirical. Further development of this PBPK model for 2-MAA in pregnant mice, in particular its scale-up to humans, will facilitate more realistic human risk assessments for the developmental toxicity of 2-ME and related compounds.

Developmental phase alters dosimetry-teratogenicity relationship for 2-methoxyethanol in CD-1 mice.

The industrial solvent 2-methoxyethanol (2-ME) elicits phase-specific terata in mice through its primary metabolite and proximate toxicant, 2-methoxyacetic acid (2-MAA). Recent pharmacokinetic studies indicate that the incidence and severity of digit malformations induced in CD-1 mice by 2-ME exposure on gestation day (gd) 11 (copulation plug = gd 0) correlate better with the total 2-MAA exposure over time (= area under the curve; AUC) than with its peak concentrations (Cmax) in maternal plasma, embryo and extraembryonic fluid. In this study, the phase specificity of exencephaly induction by 2-ME was investigated to ascertain whether the 2-ME/2-MAA dosimetry-teratogenicity relationship remains consistent throughout organogenesis. Following a single intravenous (iv) bolus dose of 250 mg 2-ME/kg given to pregnant mice, exposure on gd 8 was decidedly the gestation day that best balanced low embryo lethality and high malformation incidence as recorded in near-term fetuses. Concentrations of 2-MAA were measured during distribution and elimination in maternal plasma and conceptuses following iv bolus doses of 175, 250, and 325 mg 2-ME/kg, as well as during and after termination of subcutaneous (sc) constant-rate infusion (4, 6, and 8 hr; 8 microliters/hr) of 277, 392, and 606 mg 2-ME/kg total doses. For all administration regimens, exencephaly incidence rates were determined in fetuses on gd 18. Similar plasma 2-MAA Cmax values (approximately 5 mmol/l) and fetal malformation frequencies (approximately 12%) were induced by sc infusion of 392 mg 2-ME/kg or a bolus dose of 250 mg 2-ME/kg. However, the AUC produced by infusion was significantly larger than that following the iv bolus dose (38 vs. 26 mmol.hr/l, respectively). In both maternal plasma and conceptuses, the correlation coefficients between Cmax and exencephaly rates, as well as developmental toxicity, were higher than they were for AUC and those end points. This outcome suggests that dosimetry-teratogenicity determinants may be quite specific for a distinct developmental phase during which a particular organ differentiates and a specific chemical acts upon the embryo.